RU2820289C2 - Sulfonimidamide compounds as inhibitors of interleukin-1 activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound having the structure of formula (I-5), or a pharmaceutically acceptable salt thereof, which have the property of inhibiting inflammasome, such as NLRP3 inflammasome. In formula (I-5), R¹⁰⁰ is selected from a group consisting of H, -CN, -C(O)R^3b and C₁-C₆alkyl; R^l is selected from the group consisting of

R^1z is H; each of R^1a, R^1b, R^1c, R^1d, R^1e, R^1f, R^1g and R^1h is independently selected from a group consisting of H, -OR^11a, -NR^11aR^12a, C₁-C₆alkyl or 4-membered heterocyclyl with one ring heteroatom selected from nitrogen; where said 4-member heterocyclyl is not substituted or is substituted with one or more substitutes selected from -OR^11a; R² is selected from a group consisting of 5-member heteroaryl with two ring heteroatoms selected from nitrogen, where said 5-member heteroaryl is not substituted or is substituted with one or more substitutes selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl and -(CH₂)_1-4C₃-C₁₀cycloalkyl; X² is CR^2a ; X³ is N or CR^2c; X⁴ is CR^2d; X⁵ is N or CR^2e; R^2a is H, halogen or -C(O)OR^15a; each of R^2b, R^2c, R^2d, R^2e and R^2f independently represents H, halogen, -OR^17a, -C(O)R^17b, C₁-C₆alkyl or 5-6 membered heteroaryl with one ring heteroatom selected from nitrogen; where C₁-C₆ alkyl and said 5-6-membered heteroaryl are not substituted or are substituted with one or more substitutes selected from the group consisting of -OR_17a and -NR^17aR^18a; or two adjacent R^2b, R^2c, R^2e and R^2f together with atoms to which they are attached, can form C₃-C₁₀ cycloalkyl or 3-7-membered heterocyclyl with one ring heteroatom selected from oxygen, where C₃-C₁₀ cycloalkyl and said 3-7-membered heterocyclyl are not substituted or are substituted with one or more substitutes selected from the group consisting of halogen and C₁-C₆ alkyl; R^11a, R^12a, R^15a, R^17a and R^18a independently in each occurrence are H or C₁-C₈ alkyl; where C₁-C₈ alkyl is unsubstituted or substituted with one or more substitutes selected from the group consisting of halogen, -O-C₁-C₆alkyl and -NH(C₁-C₆alkyl); R^3b and R^17b independently in each case represent -OH or C₁-C₈ alkyl. Invention also relates to a pharmaceutical composition containing said compound.

EFFECT: disclosed are sulfonimidamide compounds as inhibitors of interleukin-1 activity.

24 cl, 6 tbl, 158 ex

Description

Cross reference to related applications

[1] This application claims priority to US Provisional Application No. 62/701313, filed July 20, 2018, the contents of which are incorporated herein by reference in their entirety.

Field of technology

[2] This invention relates to novel sulfonimimidide compounds and related compounds and their use in the treatment of a disorder susceptible to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or related components of the inflammatory process.

State of the art

[3] The NOD-like receptor (NLR) family of pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) , and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

[4] NLRP3 is an intracellular receptor protein that senses certain inflammatory signals. Once activated, NLRP3 binds to the apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC). The NLRP3–ASC complex then polymerizes to form a large aggregate known as the “ASC speck.” The polymerized NLRP3-ASC in turn interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the proinflammatory cytokines IL-1β and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis. ASC speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and initiate apoptotic cell death.

[5] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to initiate apoptosis. By regulating the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group protein 1 (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, resulting in its degradation and the ability to release IL-1α. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. A number of other caspase-1 substrates, such as cytoskeletal components and glycolytic pathways, may be involved in caspase-1-mediated inflammation.

[6] The release of NLRP3-3aBHCHMbix ASC speck occurs into the extracellular space, where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation.

[7] Active cytokines produced due to activation of the NLRP3 inflammasome are important inflammatory factors and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the proinflammatory cytokines IL-6 and tumor necrosis factor (TNF). IL-1β and IL-18 act synergistically with IL-23, inducing the production of IL-17 CD4 TH 7 memory cells (from the English T helper 17 - T-helper 17) and γδ T cells without involving the T-cell receptor. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells, mediating a Th1 response.

[8] Other intracellular pattern recognition receptors (PRRs) can also form inflammasomes. These include NLR family members such as NLRP1 and NLRC4, as well as non-NLR RRPs such as double-stranded DNA (dsDNA) sensors missing in melanoma 2 (AIM2) and interferon gamma inducible protein 16 (IFI16). NLRP3-3aBHCHMbm IL-1β processing can also be activated by an indirect non-canonical pathway downstream of caspase-11.

[9] The hereditary CAPS disease Muckle-Wels syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, thus identifying NLRP3 as an important component of the inflammatory process. NLRP3 is involved in the pathogenesis of a number of complex diseases, particularly those involving metabolic diseases such as type 2 diabetes mellitus, atherosclerosis, obesity and gout.

[10] The role of NLRP3 in central nervous system diseases is being elucidated, and NLRP3 has also been shown to influence lung diseases. In addition, NLRP3 plays a role in the development of liver disease, kidney disease and aging. Many of these relationships have been determined using mice with constitutive activation of NLRP3, but conclusions have also been drawn about specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus, deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[11] There is a need for compounds and pharmaceutical compositions with improved pharmacological and/or physiological and/or physicochemical properties and/or that are viable alternatives to existing compounds and pharmaceutical compositions.

Summary of the invention

[12] The present invention provides compounds and pharmaceutical compositions useful for inhibiting an inflammasome such as the NLRP3 inflammasome. These compounds and pharmaceutical compositions are also useful for modulating interleukins. The described compounds have the necessary molecular weight, physicochemical properties and lipophilicity, which are characteristics that help ensure therapeutic efficacy and reduce undesirable disadvantages.

[13] This invention provides a compound having the structure of formula (I),

and pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers thereof, wherein the substituents are as described herein (e.g., as described in connection with formulas (I-1), (I-2), (I-3) , (I-4), (I-5) and (I-6)).

[14] This invention provides a compound having the structure of formula (I),

or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof,

Where

R ¹ represents (i) or (ii):

(i): R ¹ is a monocyclic pyrazole of the formula

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; And

each R ^1x and R ^1y independently represents H, D, halogen, -CN, NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S( O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

(ii): R ¹ is a fused pyrazole of the formula

where (ii-a): R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl and the 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents, if present, together with the atoms to which they are attached, may form a ring; And

R ^1x represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

or (ii-b): R ^1x and R ^1y together with the atoms to which they are attached can form a C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents, if present, together with the atoms to which they attached, can form a ring; And

R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹⁰⁰ is selected from the group consisting of H, C1, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ² R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryla and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents , if present, together with the atoms to which they are attached, can form a ring;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , -P(O)R ^21b R ^22b , - S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^21a and R ^22a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -MH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; And

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^21b and R ^22b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -M(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ Cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[15] This invention provides a compound having the structure of formula (1-1),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ² R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)NR ^6a , NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S (O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C4-Cscycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3- 7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C4-Scycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O )NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl or 5 6 membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O )R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b s, -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryla and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C( O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ Cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl ), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H, D, -OH, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ , C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C^Sealkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ - C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[16] This invention provides a compound having the structure of formula (1-2),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h ,

where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S (O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ⁶ and X ⁷ represents N;

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)NR ^6a , NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S (O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl , 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl or 5-6 membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 member aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl , -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C (O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ Cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; or

two adjacent R ^2j _, R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^15a , R ^16a , R ^17a , R ^18a , R ^19a , R ^20a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -MH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b R ^4b R ^5b R ^6b R ^7b R ^8b R ^9b R ^10b R ^15b R ^17b R ^18b R ^21b R ^22b R ^23b and R ^24b are independently in each case H, D, -OH, -O(C ₁ - C ₆ alkyl), -NH ₂ , -HH(C ₁ -C ₆ alkyl), -M(C ₁ -C ₆ alkyl)2, -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ , C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[17] This invention provides a compound having the structure of formula (I-3),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, D, -Cl, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ² R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R1 is selected from the group consisting of And

R ² represents

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)NR ^6a , NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S( O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y together with the atoms to which they are attached can form a 3-7 membered heterocyclyl; wherein the 3-7 membered heterocyclyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P (O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl or 5 6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R 15a, R ^16a , R ^17a , R ^18a , R ^19a , ^{R 20a independently} in each case represent H, D , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 -membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b R ^4b R ^5b R ^6b R ^7b R ^8b R ^9b R ^10b R ^15b R ^17b R ^18b independently in each case represent H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[18] This invention provides a compound having the structure of formula (I-4),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ² R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , NR7aR8a, -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5 -6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryla and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C( O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R ^13a , R ^14a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^12b , R ^13b , R ^14b , R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H, D, -OH, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[19] This invention provides a compound having the structure of formula (I-5),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(0)R, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h ,

where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S (O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ⁶ and X ⁷ represents N;

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S( O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ Cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^3b llb, -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^3b 13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , - NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5 6-membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, C ₆ aryl or 5-membered heteroaryl, where 3-7 membered heterocyclyl and 5 -membered heteroaryl is attached to the nitrogen atom in the carbon atom in a 3-7 membered heterocyclyl or 5-membered heteroaryl and where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, C ₆ aryl or 5 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^21a , -C(O)R ^21b , -P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-membered heteroaryl;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R 13a, R ^14a , R ^15a , R ^16a , R ^17a , R ^18a , R ^21a , R ^22a , R ^23a and ^{R 24a independently} in each case represent H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^12b , R 13b ^, R ^14b , R ^15b , R ^17b , R ^18b , R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -MH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[20] This invention provides a compound having the structure of formula (I-6),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ arylaa, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ² R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² represents

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

R ^1z represents H, D, halogen, -CN, NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S( O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^3b 13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , - NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^3b 17b, -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R ^13a , R ^14a , R ^15a , R ^16a , R ^17a and R ^18a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^12b , R ^13b , R ^14b , R ^15b , R ^17b and R ^18b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryla, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[21] Provided herein are pharmaceutical compositions containing one or more of the compounds described herein, for example, the compounds of formula (I), any variations thereof described herein, one or more of compounds Nos. 1-210 in Table 1, and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, and a pharmaceutically acceptable carrier.

[22] Provided herein are methods of treating disorders, comprising the step of administering an effective amount of one or more compounds herein, for example, compounds of formula (I), any variations thereof described herein, one or more of compounds Nos. 210 in Table 1 and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, thereby treating a disorder in a subject in need thereof.

[23] Provided herein are methods for treating disorders, comprising the step of administering an effective amount of one or more pharmaceutical compositions herein to thereby treat a disorder in a subject in need thereof.

[24] Provided herein are one or more of the compounds described herein, for example, the compounds of formula (I), any variations thereof described herein, one or more of compounds Nos. 1 to 210 in Table 1, and pharmaceutically acceptable salts thereof , solvates (eg, hydrates), isomers, prodrugs and tautomers, or one or more pharmaceutical compositions herein for use in treating a disorder in a subject in need thereof.

[25] Provided herein is the use of one or more of the compounds described herein, for example, the compounds of formula (I), any variations thereof described herein, one or more of compounds Nos. 1 to 210 in Table 1, and pharmaceutically acceptable formulations thereof salts, solvates (eg, hydrates), isomers, prodrugs and tautomers for treating a disorder in a subject in need thereof.

[26] Provided herein is the use of one or more pharmaceutical compositions described herein for treating a disorder in a subject in need thereof.

[27] Provided herein is the use of one or more of the compounds described herein, for example, the compounds of formula (I), any variations thereof described herein, one or more of compounds Nos. 1 to 210 in Table 1, and pharmaceutically acceptable formulations thereof salts, solvates (eg, hydrates), isomers, prodrugs and tautomers in the manufacture of a drug for the treatment of a disorder.

[28] Provided herein is the use of one or more pharmaceutical compositions herein in the manufacture of a medicament for treating a disorder.

[29] In some embodiments, the disorder is susceptible to inflammasome inhibition.

[30] In some embodiments, the disorder is responsive to inhibition of NLRP3 inflammasome activation.

[31] In some embodiments, the disorder is a disorder of the immune system, liver, lung, skin, cardiovascular system, urinary system, gastrointestinal tract, respiratory system, endocrine system, central nervous system, or cancer or other malignancy formation, either caused by or associated with a pathogen.

[32] Provided herein are methods for modulating the activity of a biological target, comprising the step of exposing the biological target to one or more compounds described herein, for example, compounds of formula (I), any variations thereof described herein, one or more of compounds no. No. 1-210 in Table 1 and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers.

[33] Provided herein are methods for modulating the activity of a biological target, comprising the step of exposing the biological target to one or more pharmaceutical compositions as described herein.

[34] The biological target can be selected from the group consisting of NLRP3, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 inflammasome cells.

Detailed description of the invention

Definitions

[35] As used herein, the following terms, unless otherwise specified, are to be understood as having the following meanings. If the term is missing, the traditional term known to one skilled in the art is used.

[36] It should also be noted that any carbon atom, as well as any heteroatom with an unsaturated valence in the text, diagrams, examples and tables of this document, is considered to have a sufficient number of hydrogen atoms to saturate the valence.

[37] As described herein, the compounds of this invention may be optionally substituted with one or more substituents such as generally illustrated herein or exemplified by specific classes, subclasses and species of this invention. In general, the term "substituted" refers to the replacement of a hydrogen atom in a given structure with a specific substituent. Combinations of substituents provided herein are generally those that result in the formation of stable or chemically marketable compounds.

[38] As used herein, the terms “including” and “comprising” are used in an open, non-limiting sense.

[39] As used herein, the singular form may refer to one or more than one (ie, at least one) grammatical object or subject. For example, "element" can mean one element or more than one element.

[40] As used herein, the term “and/or” can mean both “and” and “or” unless otherwise indicated.

[41] For a more concise description, some quantitative expressions given herein are not accompanied by the term “about.” It should be understood that, whether the term "about" is used explicitly or not, each quantity stated herein is intended to refer to the actual specified value and is also intended to refer to an approximation of such value logically inferred one skilled in the art, including equivalents and approximations due to experimental conditions and/or measurements for such a given value. Whenever yield is given as a percentage, the yield refers to the mass of the component for which the yield is given relative to the maximum amount of the same component that can be obtained under the particular stoichiometric conditions. Concentrations are given as percentages based on weight unless otherwise noted.

[42] The term “patient” or “subject” can include both mammals and non-mammals. Examples of mammals may include, but are not limited to, any members of the class Mammalia: humans, non-human primates such as chimpanzees, marmosets, baboons or rhesus macaques, as well as other species of monkeys and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; companion animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; and so on. Examples of non-mammalian animals include, but are not limited to, birds, fish, etc. The term "patient" or "subject" can include both humans and animals. In some embodiments, the patient or subject is a human.

[43] The term "inhibition" can refer to a molecule, such as a compound, drug, enzyme or hormone, that blocks or otherwise interferes with a particular biological activity.

[44] The terms "effective amount" or "therapeutically effective amount" as used in connection with compounds or pharmaceutical compositions can refer to a sufficient amount of one or more compounds or one or more pharmaceutical compositions to provide the desired biological effect. This result may be a reduction and/or lessening of the intensity of signs, symptoms or causes of the disorder or any other necessary change in the biological system. For example, an "effective amount" for a therapeutic use may be the amount of a pharmaceutical composition containing one or more compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers described herein necessary to provide clinically significant reduction in the intensity of the disease. The appropriate "effective amount" in each individual case can be determined by one skilled in the art using routine experimentation. Thus, the term "effective amount" may generally refer to the amount in which the active substance has a therapeutic effect. In the present case, the active substance may be an inflammasome inhibitor.

[45] As used herein, the terms “treat” or “cure” are intended to indicate slowing the progression of the disorder; preventing the development of disorders; and/or reducing the severity of such symptoms that will or are expected to develop. Thus, these terms may include reducing the intensity of existing symptoms of a disorder; preventing the appearance of additional symptoms; reducing the intensity or preventing the primary causes of symptoms; inhibiting the disorder, for example, stopping the development of the disorder; relief of disorder; ensuring regression of the violation; relief of symptoms caused by the disorder; or elimination or alleviation of symptoms of a disorder.

[46] The terms "pharmaceutically acceptable" or "pharmacologically acceptable" may refer to a material that is not biologically or otherwise objectionable, that is, the material can be administered to a subject without causing any inherently undesirable biological effects or does not interact in an unacceptable manner with any other components of the composition in which it is contained.

[47] As used herein, the term "carrier" may include carriers, excipients and diluents and may mean a material, composition or carrier medium, for example, a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transport of a pharmaceutical agent, such as one or more compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers thereof of this invention, from one organ or body part to another organ or other body part of a subject. Carriers should be selected based on the compatibility and release profile properties of the desired dosage form. Typical carrier materials may include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[48] As used herein, the term “IC ₅₀ ” may refer to concentrations at which the activity, phenotype or response being measured, for example, growth or proliferation of cells, such as tumor cells, is inhibited by 50%. IC ₅₀ values can be estimated from an appropriate dose-response curve, for example by eye or using appropriate curve fitting or statistical software. More accurate IC ₅₀ values can be determined using nonlinear regression analysis.

[49] As used herein, the terms “administered,” “administered,” or “administered” may refer to both the direct administration to a subject of one or more compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers, and pharmaceutical compositions according to the invention.

[50] As used herein, “alkyl” can mean a straight chain or a saturated branched chain containing from 1 to 10 carbon atoms. Typical saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2 -pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl , t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and longer alkyl groups such as heptyl, octyl, etc. An alkyl group may be unsubstituted or substituted. Alkyl groups containing three or more carbon atoms may be straight or branched. As used herein, "lower alkyl" means an alkyl containing from 1 to 6 carbon atoms.

[51] As used herein, "alkenyl" may comprise a straight or branched hydrocarbon chain containing 2-12 carbon atoms. An "alkenyl" group contains at least one double bond. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups may include, but are not limited to, ethylenyl, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl, etc. The alkenyl group may be unsubstituted or substituted. Alkenyl, as defined herein, may also be branched or straight-chain.

[52] As used herein, "alkynyl" may comprise a straight or branched unsaturated hydrocarbon chain containing 2-12 carbon atoms. An "alkynyl" group contains at least one triple bond. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl, and the like. The alkynyl group may be unsubstituted or substituted.

[53] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[54] The term "haloalkyl" refers to an alkyl radical as defined above, which is substituted by one or more radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3 -bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[55] The term “ring atoms,” when used in conjunction with the terms relating to the ring systems described herein (eg, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl), refers to the total number of ring atoms present in the system. Therefore, "ring atoms" do not include atoms present in the substituent attached to the ring. Thus, the number of "ring atoms" includes all the atoms present in the fused ring. For example, a 2-indolyl ring, is considered a 5-membered heteroaryl, but is also a heteroaryl containing 9 ring atoms. In another example, pyridine is considered a 6-membered heteroaryl and is a heteroaryl containing 6 ring atoms.

[56] "Cycloalkyl" refers to a single saturated one-carbon ring containing 3-20 ring carbon atoms (i.e., C ₃ -C ₂₀ cycloalkyl), e.g., 3-15 ring atoms, e.g., 3-12 ring atoms atoms. In certain embodiments, the cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl"), and may be saturated. "Cycloalkyl" includes ring systems in which the cycloalkyl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, the point of attachment being on the cycloalkyl ring, and in such cases the number of carbon atoms indicated also denotes the number of atoms carbon in the cycloalkyl ring containing the point of attachment. Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl 2-(2,3-dihydro-1H-indene) and 9-fluorenyl As stated above, cycloalkyl rings can be further characterized by the number of ring atoms. For example, a cyclohexyl ring is a C ₆ cycloalkyl ring with 6 ring atoms, while 2-(2,3-dihydro-1H-indene) is a C ₅ cycloalkyl ring with 9 ring atoms. Also, for example, 9-fluorenyl is a C ₅ cycloalkyl ring with 13 ring atoms, and 2-adamantyl is a C ₆ cycloalkyl ring with 10 ring atoms.

[57] In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-10 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-12 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkyl has 3-7 ring atoms. In certain embodiments, the C ₃ -C ₉ cycloalkyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₉ cycloalkyl has 3-10 ring atoms. In certain embodiments, the C ₃ -C ₉ cycloalkyl has 3-9 ring atoms. In certain embodiments, the C ₃ -C ₈ cycloalkyl has 3-8 ring atoms. In certain embodiments, the C ₃ -C ₈ cycloalkyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkyl has 3 to 14 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkyl has 3-10 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkyl has 3-7 ring atoms.

[58] As used herein, the term “cycloalkenyl” may refer to a partially saturated, monocyclic, fused or spiro-polycyclic, single carbon ring containing 3-18 carbon atoms per ring and at least one double bond. "Cycloalkenyl" includes ring systems in which the cycloalkenyl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, the point of attachment being on the cycloalkenyl ring, and in such cases the number of said carbon atoms also denotes the number of atoms carbon in the cycloalkenyl ring containing the point of attachment. Cycloalkenyl rings can be further characterized by the number of ring atoms. Examples of cycloalkenyls include 1-cyclohex-1-enyl and cyclopent-1-enyl.

[59] In certain embodiments, the cycloalkenyl has 3-14 ring atoms. In certain embodiments, the cycloalkenyl has 3-10 ring atoms. In certain embodiments, the cycloalkenyl has 3-9 ring atoms. In certain embodiments, the cycloalkenyl has 3-7 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkenyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkenyl has 3 to 10 ring atoms. In certain embodiments, the C ₃ -C ₉ cycloalkenyl has 3-9 ring atoms. In certain embodiments, the C ₃ -C ₈ cycloalkenyl has 3-8 ring atoms. In certain embodiments, the C ₃ -C ₈ cycloalkenyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkenyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkenyl has 3-10 ring atoms. In certain embodiments, the C ₃ -C ₇ cycloalkenyl has 3-7 ring atoms.

[60] As used herein, the term “aryl” refers to a single carbon ring or multiple fused single carbon ring systems in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 5-20 ring carbon atoms, 5-14 ring carbon atoms, or 5-12 ring carbon atoms. Aryl also includes multiple fused ring systems (e.g., systems containing 2, 3, or 4 rings) containing 9-20 carbon atoms, in which at least one ring is aromatic and the other rings may be aromatic or non-aromatic (i.e. e. cycloalkyl). "Aryl" includes ring systems in which the aryl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, the point of attachment being on the aryl ring, and in such cases the number of carbon atoms indicated also denotes the number of atoms carbon on the aryl ring containing the point of attachment. Examples of aryl groups include phenyl and 5-(2,3-dihydro-1H-indene): As stated above, aryl rings can be further characterized by the number of ring atoms. For example, phenyl is a C6 _- aryl with 6 ring atoms, while 5-(2,3-dihydro-1H-indene) is a _C6- aryl with 9 ring atoms.

[61] In certain embodiments, the aryl ring is C ₆ aryl with 6 to 14 ring atoms. In certain embodiments, the aryl ring is C ₆ aryl with 6-10 ring atoms. In certain embodiments, the aryl ring is C ₆ aryl with 6-12 ring atoms. In certain embodiments, the aryl ring is a C ₆ aryl with 6 ring atoms.

[62] As used herein, “heterocyclyl” refers to a single saturated or partially unsaturated non-aromatic ring or multiple non-aromatic ring system that has at least one heteroatom in the ring (at least one ring heteroatom selected from oxygen, nitrogen and sulfur) . Unless otherwise specified, a heterocyclyl group has from 5 to about 20 ring atoms, such as from 5 to 15 ring atoms, such as from 5 to 10 ring atoms. Thus, the term includes saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 ring carbon atoms per ring and about 1 to 3 ring carbon atoms. heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The term also includes saturated or partially unsaturated rings (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered rings) having from about 4 to 9 ring carbon atoms in the ring and from about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. "Heterocyclyl" includes ring systems in which the heterocyclyl ring as defined above is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, the point of attachment being on the heterocyclic ring, and in such cases the number of said ring members also denotes the number of ring members atoms in a heterocyclic ring containing an attachment point. Heterocyclic rings can be further characterized by the number of ring atoms. Examples of heterocyclic rings include piperidinyl (6-membered heterocycle with 6 ring atoms), azepanyl (7-membered heterocycle with 7 ring atoms) and 3-chromnyl (6-membered heterocycle with 10 ring atoms)

[63] In certain embodiments, a 3-7 membered heterocyclyl has 3-7 ring atoms. In certain embodiments, a 3-6 membered heterocyclyl has 3-6 ring atoms. In certain embodiments, the 3-5 membered heterocyclyl has 3-5 ring atoms. In certain embodiments, the 3-5 membered heterocyclyl has 3-9 ring atoms. In certain embodiments, the 3 7 membered heterocyclyl has 3-14 ring atoms. In certain embodiments, the 3-7 membered heterocyclyl has 3-12 ring atoms. In certain embodiments, the 3-7 membered heterocyclyl has 3-10 ring atoms.

[64] As used herein, the term “heteroaryl” refers to a single aromatic ring that has at least one ring atom other than carbon, which atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple fused ring systems that have at least one such aromatic ring. Thus, the term includes single heteroaryl rings of 1-6 ring carbon atoms and about 1-4 ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Sulfur and nitrogen atoms may also be present in oxidized form, provided the ring is aromatic. "Heteroaryl" includes ring systems in which the heteroaryl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, the point of attachment being on the heteroaryl ring, and in such cases the number of ring members also denotes the number of ring members on a heteroaryl ring containing an attachment point. Heteroaryl rings can be further characterized by the number of ring atoms. For example, pyridine is a 6-membered heteroaryl containing 6 ring atoms.

[65] In certain embodiments, the heteroaryl ring is a 5-6 membered heteroaryl with 5-15 ring atoms. In certain embodiments, the heteroaryl ring is a 5-6 membered heteroaryl with 5-10 ring atoms. In certain embodiments, the heteroaryl ring is a 5-6 membered heteroaryl with 5-6 ring atoms. In certain embodiments, the heteroaryl ring is a 5-6 membered heteroaryl with 5-12 ring atoms. In certain embodiments, the heteroaryl ring is a 5-membered heteroaryl with 5-15 ring atoms. In certain embodiments, a 5-membered heteroaryl has 5 ring atoms. In certain embodiments, a 5-membered heteroaryl has 5-8 ring atoms. In certain embodiments, the 5-membered heteroaryl has 5-9 ring atoms. In certain embodiments, a 5-membered heteroaryl has 5-10 ring atoms. In certain embodiments, the 5-membered heteroaryl has 5-12 ring atoms. In certain embodiments, the heteroaryl ring is a 6-membered heteroaryl with 6-15 ring atoms. In certain embodiments, the heteroaryl ring is a 6-membered heteroaryl with 6-10 ring atoms. In certain embodiments, the heteroaryl ring is a 6-membered heteroaryl with 6-14 ring atoms. In certain embodiments, the 6-membered heteroaryl has 6-13 ring atoms. In certain embodiments, a 6-membered heteroaryl has 6 ring atoms. In certain embodiments, a 6-membered heteroaryl has 6-9 ring atoms. In certain embodiments, a 6-membered heteroaryl has 6-10 ring atoms. In certain embodiments, the 6-membered heteroaryl has 6-12 ring atoms.

[66] As used herein, numeric ranges may include sequential integers. For example, a range expressed as "0 to 5" would include 0, 1, 2, 3, 4, and 5.

[67] As used herein, the term “unsubstituted” may mean that a particular group does not bear substituents beyond the designated moiety (eg, if the valency is hydrogen saturated).

[68] As used herein, the term “oxo” refers to the “=O” group. It may also be abbreviated herein as C(O) or C=O.

[69] This invention relates to the compounds described herein and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers, as well as pharmaceutical compositions containing one or more compounds described herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers.

[70] This invention relates to the compounds described herein and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers, prodrugs or tautomers. It is intended that the use of the terms "salt", "hydrate", "prodrug", "ester" and the like apply equally to the salt, hydrate, solvate, prodrug or ester of enantiomers, isomers, prodrugs, rotamers, tautomers, positional isomers or racemates of the described compounds.

[71] It should be understood that all isomeric forms, including mixtures thereof, are included in this invention. The term "isomer" can refer to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be manifested in structure (geometric or positional isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of the invention may have one or more asymmetric carbon atoms and may be in the form of racemates, racemic mixtures, and as individual enantiomers or diastereomers. Individual isomers of the compounds of the invention may, for example, contain essentially no other isomers, or may be mixed, for example, as racemates with all the other or other selected isomers. If the compound contains a double bond, the substituent may be in the E or Z configuration, or in the cis or trans configuration, or a mixture of the above. The analytical results described may represent data obtained for the racemic form, the enantiomerically pure form, or any form in terms of stereochemistry or structure (eg, geometric or positional isomers).

[72] The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. The term "stereoisomers" can refer to a group of compounds that have the same number and type of atoms and have the same bonds between those atoms, but differ in three-dimensional structure. The term "stereoisomer" can refer to any member of this group of compounds. For example, a stereoisomer may be an enantiomer or a diastereomer. All stereoisomeric forms of the compounds of the invention, as well as mixtures thereof, including racemic mixtures, are intended to form part of the invention.

[73] The term "enantiomers" can refer to a pair of stereoisomers that are not compatible mirror images of each other. The term "enantiomer" can refer to one member of this pair of stereoisomers. The term "racemic" can refer to a 1:1 mixture of a pair of enantiomers. Each compound described herein includes all enantiomers (which may exist even in the absence of asymmetric carbon atoms) that correspond to the general structure of the compound unless stereochemistry is explicitly stated. The compounds may be in racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The chiral centers of this invention may have the S or R configuration as defined in the IUPAC 1974 Recommendations. In some of the examples presented, the synthetic process may produce a single enantiomer or a mixture of enantiomers. In some embodiments, the compounds of the invention are enantiomers. In some embodiments, the compounds of the invention are (S)-enantiomers. In some embodiments, the compounds of the invention are (+)-enantiomers. In some embodiments, the compounds of the invention may be (+) or (-) enantiomers.

[74] The term "diastereomers" can refer to a group of stereoisomers that cannot be compatible by rotating around single bonds. For example, cis- and trans-double bonds, endo- and exo-substitution in bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations can be considered diastereomers. The term "diastereomer" can refer to any member of this group of compounds. In some of the examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The present invention may include diastereomers of the compounds described herein.

[75] In some embodiments, the pharmaceutical compositions of the invention may be fortified to contain predominantly one enantiomer of a compound described herein. An enantiomerically enriched mixture may contain, for example, at least 60 mole percent of one enantiomer, or more preferably at least 75, at least 80, at least 85, at least 90, at least 95, at least 96 , at least 97, at least 98, at least 99, at least 99.5 or even 100 mole percent. In some embodiments, compositions described herein that are enriched for one enantiomer may be substantially free of the other enantiomer, where "substantially free" may mean that the substance in question is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in a pharmaceutical composition or mixture of the compound. For example, if a pharmaceutical composition or mixture of a compound contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it is said to contain 98 mole percent of the first enantiomer and only 2 mole percent of the second enantiomer.

[76] In some embodiments, the pharmaceutical compositions of the invention may be fortified to contain predominantly one diastereomer of a compound described herein. A diastereomerically enriched mixture may contain, for example, at least 60 mole percent of one diastereomer, or more preferably at least 75, at least 80, at least 85, at least 90, at least 95, at least 96 , at least 97, at least 98, at least 99, at least 99.5 or even 100 mole percent. In some embodiments, compositions described herein that are enriched for one diastereomer may be substantially free of other diastereomers, whereby "substantially free" may mean that the substance in question is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of other diastereomers, for example, in the pharmaceutical composition or mixture of the compound.

[77] Diastereomeric mixtures can be separated into individual diastereomers based on their physical or chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture to a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers . Enantiomers can also be separated using a chiral HPLC column. Also, some of the compounds of the invention may be atropoisomers or rotameric forms and are considered part of this invention.

[78] The compounds of the invention may exist in rotameric form (eg, amide or imino ester). All such tautomeric forms are provided herein as part of the present invention. Also included, for example, in this invention are keto-enol and imine-enamine forms of the compounds. It should also be noted that the sulfonimidyl ureas described herein have tautomeric forms. The structures have been graphically represented as a single form in this document, but it should be noted that tautomers can exist in equilibrium. For example, are tautomers. All tautomeric forms for each compound are covered, although only one tautomeric form may be represented for each compound, which may be a major tautomeric form or a minor tautomeric form.

[79] This invention may include pharmaceutically acceptable salts of the compounds described herein. A “pharmaceutically acceptable salt” may be acceptable for use in humans or pets and may refer to those salts that retain biological effectiveness and free form properties that are not biologically or otherwise objectionable. Exemplary "pharmaceutically acceptable salts" may include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate , bromide, butyrate, calcium salts, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium salts, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, 1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

[80] Pharmaceutically acceptable salts may include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salt" may refer to those salts that retain the biological effectiveness and free base properties that are not biologically or otherwise undesirable and that can be formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid , benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carboxylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid , glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2- sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.

[81] "Pharmaceutically acceptable base addition salt" may refer to those salts that retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. These salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like salts. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium and manganese salts. Salts derived from organic non-toxic bases may include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine , triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, min, theobromine , triethanolamine, tromethamine, purines, piperisine, piperidine, N-ethylpiperidine, polyamine resins, etc.

[82] The present invention may include zwitterions of the compounds described herein. "Zwitterion" can refer to a molecule that has both positively charged and negatively charged groups, but has no net charge, i.e. The + and - charges in the molecule are balanced. For example, the compounds of the invention may contain protonated amino groups and deprotonated sulfate groups.

[83] The compounds of the invention may exist as solvates. The term "solvate" may refer to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents, for the purposes of the invention, may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates in which the solvent molecule is water are usually called hydrates. Hydrates may include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[84] The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds. An "isotope-labeled" or "radiolabeled" compound may be a compound in which one or more atoms are replaced or replaced by an atom having an atomic mass or atomic number different from the atomic mass or atomic number found in nature (i.e., natural origin). For example, in some embodiments, in the compounds described herein, hydrogen atoms are replaced or replaced by one or more deuterium or tritium atoms. Certain isotope-labeled compounds of this invention, for example those in which a radioactive isotope is included, may be useful in tissue distribution studies of drug and/or substrate. Radioactive isotopes of tritium, i.e. ³ H, and carbon 14, i.e. ¹⁴ C may be particularly useful for this purpose due to the ease of their inclusion and the availability of off-the-shelf detection tools. Substitution with heavier isotopes such as deuterium, i.e. ^2H may provide certain therapeutic benefits as a result of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be advantageous in some circumstances. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compound of this invention may be replaced or replaced by a deuterium atom. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Suitable isotopes that may be included in the compounds described herein include, but are not limited to, ^2H (also referred to as D-deuterium), ^3H (also referred to as T-tritium), ^11C , ^13C , ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ^l8 O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in positron emission tomography (PET) studies.

[85] Isotopically labeled compounds from the compounds described herein can generally be prepared by following procedures similar to those described in the Schemes and/or Examples herein by substituting the corresponding isotope-labeled reagent for the non-isotopically labeled reagent.

Connections

[86] This invention provides a compound having the structure of formula (I),

and pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers thereof, wherein the substituents are as described herein (e.g., as described in connection with formulas (I-1), (I-2), (I-3) , (I-4), (I-5) and (I-6)).

[87] In one aspect, there is provided a compound having the structure of formula (I),

or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein

R ¹ represents (i) or (ii):

(i): R ¹ is a monocyclic pyrazole of the formula

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; And

each R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO2, -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S( O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

(ii): R ¹ is a fused pyrazole of the formula

where (ii-a): R ^1w and R ^1y , together with the atoms to which they are attached, can form 3 7-membered heterocyclyl or 5-6-membered heteroaryl; wherein the 3-7 membered heterocyclyl and the 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents, if present, together with the atoms to which they are attached, may form a ring; And

R ^1x represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S( O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

or (ii-b): R ^1x and R ^1y together with the atoms to which they are attached can form a C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents, if present, together with the atoms to which they attached, can form a ring; And

R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(C-)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents or, optionally, two of the substituents , if present, together with the atoms to which they are attached, can form a ring;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^21a and R ^22a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; And

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^21b and R ^22b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[88] In some embodiments, the compound is different from the compound in Table 1X and its pharmaceutically acceptable salts, solvates, isomers, and tautomers. In some embodiments, a compound herein, such as a compound of Formula (I), is different from a compound selected from one or more of Compounds Nos. 1x-30x in Table IX and their pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers. In some embodiments, the compounds of the invention and the methods of using the compounds described herein include any of the compounds of formula (I), including those listed in Table 1 and their pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers.

[89] In one aspect, there is provided a compound of formula (I) or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., a hydrate), prodrug, metabolite, or derivative thereof, wherein R ² is as defined herein and R ¹ is is a monocyclic pyrazole, which is optionally substituted as described herein. In one embodiment, the compound is different from a compound selected from one or more of Compounds Nos. 1x-30x in Table 1X and their pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers. In some embodiments, R ² is 4-pyrazolyl, which is optionally substituted as described herein, as long as R ¹ is other than 1,3-dimethylpyrazol-4-yl. In some embodiments, R ² is 4-pyrazolyl, which is optionally substituted as described herein, so long as the compound is different from compound 1x in Table 1 and its pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers. In some embodiments, R ² is 3-pyrazolyl, which is optionally substituted as described herein, provided that the compound is different from a compound selected from one or more of compounds 2x-30x in Table 1 and pharmaceutically acceptable salts, solvates thereof , isomers, prodrugs and tautomers.

[90] In some embodiments, R ¹⁰⁰ is H, -CN, -C(O)R ^3b or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is unsubstituted or substituted with C ₆ aryl. In one embodiment, R ¹⁰⁰ is H.

[91] In some embodiments, R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl, and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR, -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O )NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5- 6-membered heteroaryl;

R ^23a and R ^24a independently in each case represent H, D, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; And

R ^23b and R ^24b independently in each case represent H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ - C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[92] In some embodiments, R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h , where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3 7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ - C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S(O ) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ⁶ and X ⁷ represents N;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -P(O)R ^15b R ^16b , -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S (O) ₂ R ^16a wherein C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C( O)R ^15b , -P(O)R ^15b R ^16b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ; each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ; R ^15a , R ^16a , R ^17a , R ^18a , R ^19a and R ^20a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; And

R ^15b , R ^16b , R ^17b and ^18b are independently in each case, H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3 7-membered heterocyclyl or 5 6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[93] In some embodiments, R ^2a is H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C (O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[94] In some of these embodiments, R ^2a is H, halogen, -CN, -OR ^15a , -C(O)OR ^15a or C ₁ -C ₆ alkyl; where the C ₁ -C ₆ alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -P(O)R ^15b R ^16b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[95] In some of these embodiments, R ^2a is H, halogen, -CN, -OR ^15a , -C(O)OR ^15a or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl. In one embodiment, R ^2a is H or F. In another embodiment, R ^2a is H. In another embodiment, R ^2a is F.

[96] In some embodiments, R ² is selected from the group consisting of And

[97] In some embodiments, R ² is In some of these embodiments, X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2e . In one embodiment, R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl and -CN. In some of these embodiments, R ² is selected from the group consisting of And

[98] In some of these embodiments, X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2e , where:

R ^2b and R ^2c, together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ; And

each R ^2d , R ^2e and R ^2f independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O )OR ^18a , -NR ^17a C(O)NR ^18a , NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

In some of these embodiments, R ² is selected from the group consisting of And

[99] In some of these embodiments, X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2e , where:

R ^2b and R ^2c, together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

R ^2e and R ^2f, together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ; And

R ^2d represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C (O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

In some of these embodiments, R ² is selected from the group consisting of And . In some of these embodiments, R ² is selected from the group consisting of , And .

[100] In some embodiments, R ² is X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; X ⁵ represents CR ^2e ; a R ² is selected from the group consisting of , And

[101] In some embodiments, where R ² is , X ³ represents N and X ⁴ represents CR ^2d . In some of these embodiments, X ⁵ is CR ^2e . In some of these embodiments, X ⁵ is N. In some of these embodiments, R ² is selected from the group consisting of And .

[102] In one aspect, a compound of formula (I) or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., a hydrate), prodrug, metabolite, or derivative thereof is provided, wherein R ² is as defined herein and R ¹ is is a monocyclic pyrazole with the formula or where R ^1w , R ^1x and R ^1y are discrete substituents. In some of these embodiments, R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; and each of R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O) NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ alkynyl, C ₂ -C ₆ alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ alkynyl, C ₂ -C ₆ alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[103] In one aspect, there is provided a compound of formula (I) or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., a hydrate), prodrug, metabolite, or derivative thereof, wherein R ² is as defined herein and R ¹ is is a fused pyrazole with the formula or where any R ^1w and R ^1y together with the atoms to which they are attached can form a fused ring or R ^1x and R ^1y together with the atoms to which they are attached can form a fused ring.

[104] In some of these embodiments, R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl and a 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl and the 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two substituents, if present, together with the atoms to which they are attached, may form a ring; and R ^1x is H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl. In some embodiments, R ^1w and R ^1y, together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl and the 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a .

[105] In some of these embodiments, R ^1x and R ^1y , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents or, optionally, two substituents, if present, together with the atoms to which they are attached, can form a ring; and R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl. In some embodiments, R ^1x and R ^1y, together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a .

[106] In some embodiments, a compound of formula (I) or a salt (eg, a pharmaceutically acceptable salt), solvate (eg, a hydrate), prodrug, metabolite, or derivative thereof is provided, wherein R ² is as defined herein and R ¹ selected from the group consisting of

And

where R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 -membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a , R ^1b ; R ^1c , R ^1d ' R ^1e , R ^1f ; R ^1g and R ^1h , if present, may form an oxo group;

R ^7a , R ^8a , R ^11a , R ^12a , R ^13a and R ^14a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3 7-membered heterocyclyl and 5-6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^7b , R ^8b , R ^11b , R ^12b , R ^13b and R ^14b independently in each case represent H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[107] The present invention provides a compound having the structure of formula (I-1),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S (O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C4-Cscycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3- 7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl or 5-6 membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3 7-membered heterocyclyl and 5-6-membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl , -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C (O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C( O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S (O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H, D, -OH, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[108] The present invention provides a compound having the structure of formula (I-2),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h , And ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S (O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ⁶ and X ⁷ represents N;

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S (O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl , 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl or 5-6 membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^15a , R ^16a , R ^17a , R ^18a , R ^19a , R ^20a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^15b , R ^17b , R ^18b R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H , D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5 -6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[109] The present invention provides a compound having the structure of formula (I-3),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, D, -Cl, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² represents

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

where R ^1w is selected from the group consisting of H, D, -CN, C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S( O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C2-Sbalkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 -membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y together with the atoms to which they are attached can form a 3-7 membered heterocyclyl; wherein the 3-7 membered heterocyclyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P (O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ^2a represents H, D, halogen, -CN, OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5 6-membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^{10a, R 15a} , R ^16a , R ^17a , R ^18a , R ^19a and ^{R 20a are} independently in each case H, D , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 -membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^15b , R ^17b and R ^18b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[110] The present invention provides a compound having the structure of formula (I-4),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

And

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S( O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C( O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, - CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S (O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R ^13a , R ^14a , R ^21a , R ^22a , R ^23a and R ^24a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^12b , R ^13b , R ^14b , R ^21b , R ^22b , R ^23b and R ^24b are independently in each case H, D, -OH, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[111] The present invention provides a compound having the structure of formula (I-5),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

And

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h , And where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S (O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ independently represent N or CR ²ⁿ where at least one of X ⁶ and X ⁷ represents N;

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5 6-membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; R ^1g and R ^1h , if present, may form an oxo group;

R ^2a represents H, D, halogen, -CN, OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O)R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, C ₆ aryl or 5-membered heteroaryl, where 3-7 membered heterocyclyl and 5 -membered heteroaryl is attached to the nitrogen atom in the carbon atom in a 3-7 membered heterocyclyl or 5-membered heteroaryl and where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, C ₆ aryl or 5 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^21a , -C(O)OR ^21b , -P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22b , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5 membered heteroaryl;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R 13a, R ^14a , R ^15a , R ^16a , R ^17a , R ^18a , R ^21a , R ^22a , R ^23a and ^{R 24a independently} in each case represent H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^l2b , R ^l3b , R ^{14b , R 15b , R 17b , R 18b , R 21b , R 22b , R 23b and R 24b are independently in each} case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[112] The present invention provides a compound having the structure of formula (I-6),

and its pharmaceutically acceptable salts, solvates, isomers, prodrugs and tautomers, wherein:

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a , -NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ¹ is selected from the group consisting of

R ² represents

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^l3b , -S(O)R ^l3b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ^2a represents H, D, halogen, -CN, OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^l6a , -C(O)OR ^15a , -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O)R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , - NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

R ^3a , R ^4a , R ^7a , R ^8a , R ^11a , R ^12a , R ^13a , R ^14a , R ^15a , R ^16a , R ^17a and R ^18a are independently in each case H, D, C ₁ -C ₃ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)2, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl;

R ^3b , R ^4b , R ^7b , R ^8b , R ^11b , R ^12b , R ^13b , R ^14b , R ^15b , R ^17b and R ^18b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[113] In certain embodiments, R ¹ is selected from the group consisting of

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8b , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -nr ^11a c(o)or ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two of the following groups, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , when present, together with the atoms to which they are attached, may form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ^7a , R ^8a , R ^11a , R ^12a , R ^13a and R ^14a are independently in each case H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^7b , R ^8b , R ^11b , R ^12b , R ^13b and R ^14b are independently in each case H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[114] In certain embodiments, R ¹⁰⁰ is H. In certain embodiments, R ¹⁰⁰ is C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl. In certain embodiments, R ¹⁰⁰ is C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkyl is unsubstituted or substituted with C ₆ aryl.

[115] As described above, R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C( O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl.

[116] In certain embodiments, R ² is a 6-membered heteroaryl. In certain embodiments, a 6-membered heteroaryl has 6-10 ring atoms. In certain embodiments, a 6-membered heteroaryl has 6-9 ring atoms. In certain embodiments, a 6-membered heteroaryl has 6 ring atoms.

[117] In certain embodiments, R ² is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms. In certain embodiments, R ² is a 6-membered heteroaryl containing 1 nitrogen atom. In certain embodiments, R ² is a 6-membered heteroaryl containing 2 nitrogen atoms.

[118] In certain embodiments, the 6-membered heteroaryl is where X ³ represents N or CR ^2c ; X ⁴ represents N or CR ^2d ; X ⁵ represents N or CR ^2e ; and X ⁶ and X ⁷ are independently N or CR ²ⁿ .

[119] In certain embodiments, R ² is an unsubstituted or substituted 6-membered heteroaryl, wherein the 6-membered heteroaryl is selected from the group consisting of And

In certain embodiments, R ² is a 6-membered heteroaryl substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ aryl, -OR ^23a , C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, -CN and -NR ^23a R ^24a .

[120] In certain embodiments, R ² is C ₆ aryl. In certain embodiments, the aryl ring is C ₆ -aryl with 6-14 ring atoms. In certain embodiments, the aryl ring is C ₆ aryl with 6-10 ring atoms. In certain embodiments, the aryl ring is C ₆ aryl with 6-12 ring atoms. In certain embodiments, the aryl ring is a C ₆ aryl with 6 ring atoms.

[121] In certain embodiments, R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, -NR ^2g R ^2h ,

[122] In certain embodiments, R ² is where X ³ represents N or CR ^2c ; X ⁴ represents N or CR ^2d ; X ⁵ represents N or CR ^2e ; and X ⁶ and X ⁷ are independently N or CR ²ⁿ .

[123] In certain embodiments, R ² is C ₁ -C ₆ alkyl. In certain embodiments, R ² is C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In certain embodiments, R ² is C ₁ -C ₆ alkyl substituted with one or more C ₆ aryls.

[124] In certain embodiments, R ² is C ₃ -C ₁₀ cycloalkyl. In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-14 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-12 ring atoms. In certain embodiments, the C ₃ -C ₁₀ cycloalkyl has 3-10 ring atoms. In certain embodiments, R ² is C ₃ -C ₉ cycloalkyl with 3-9 ring atoms. In certain embodiments, R ² is C ₃ -C ₉ cycloalkyl with 3-14 ring atoms. In certain embodiments, R ² is C ₃ -C ₉ cycloalkyl with 3-10 ring atoms. In certain embodiments, R ² is C ₃ -C ₈ cycloalkyl with 3-8 ring atoms. In certain embodiments, R ² is C ₃ -C ₈ cycloalkyl with 3-14 ring atoms. In certain embodiments, R ² is C ₃ -C ₇ cycloalkyl with 3-14 ring atoms. In certain embodiments, R ² is C ₃ -C ₇ cycloalkyl with 3-10 ring atoms. In certain embodiments, R ² is C ₃ -C ₇ cycloalkyl with 3-7 ring atoms.

[125] In certain embodiments, R ² is C ₅ cycloalkyl, C ₆ cycloalkyl, or C ₇ cycloalkyl.

[126] Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl 2-(2,3-dihydro-1H-indene) and 9- fluorenyl As stated above, cycloalkyl rings can be further characterized by the number of ring atoms. For example, a cyclohexyl ring is a C ₆ cycloalkyl ring with 6 ring atoms, while 2-(2,3-dihydro-1H-indene) is a C ₅ cycloalkyl ring with 9 ring atoms. Also, for example, 9-fluorenyl is a C ₅ cycloalkyl ring with 13 ring atoms, and 2-adamantyl is a C ₆ cycloalkyl ring with 10 ring atoms.

[127] In certain embodiments, R ² is unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, wherein C ₃ -C ₁₀ cycloalkyl is selected from the group consisting of In certain embodiments, R ² is C ₃ -C ₁₀ cycloalkyl, substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl and C ₆ aryl.

[128] In certain embodiments, R ² is a 3-7 membered heterocyclyl. In certain embodiments, a 3-7 membered heterocyclyl has 3-7 ring atoms. In certain embodiments, the 3-7 membered heterocyclyl has 3-14 ring atoms. In certain embodiments, the 3-7 membered heterocyclyl has 3-12 ring atoms. In certain embodiments, the 3-7 membered heterocyclyl has 3-10 ring atoms. In certain embodiments, R ² is a 3-6 membered heterocyclyl. In certain embodiments, a 3-6 membered heterocyclyl has 3-6 ring atoms. In certain embodiments, R2 is a 3-5 membered heterocyclyl. In certain embodiments, the 3-5 membered heterocyclyl has 3-5 ring atoms. In certain embodiments, the 3-5 membered heterocyclyl has 3-9 ring atoms.

[129] In certain embodiments, R ² is an unsubstituted or substituted 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is selected from the group consisting of In certain embodiments, R ² is a 3-7 membered heterocyclyl substituted with one or more C ₁ -C ₆ alkyls

[130] In certain embodiments, R ² is a 5-membered heteroaryl. In certain embodiments, a 5-membered heteroaryl has 5 ring atoms. In certain embodiments, a 5-membered heteroaryl has 5-8 ring atoms. In certain embodiments, the 5-membered heteroaryl has 5-9 ring atoms. In certain embodiments, a 5-membered heteroaryl has 5-10 ring atoms. In certain embodiments, the 5-membered heteroaryl has 5-12 ring atoms.

[131] In certain embodiments, R ² is a 5-membered heteroaryl containing 1 or 2 nitrogen atoms. In certain embodiments, R ² is a 5-membered heteroaryl containing 1 nitrogen atom. In certain embodiments, R ² is a 5-membered heteroaryl containing 2 nitrogen atoms.

[132] In certain embodiments, R ² is an unsubstituted or substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from the group consisting of In certain embodiments, R ² is a 5-membered heteroaryl substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ aryl and -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl .

[133] In certain embodiments, R ² is a 5-membered heteroaryl selected from the group consisting of

[134] In certain embodiments, R ² is X ⁶ and X ⁷ are independently N or CR ²ⁿ , wherein at least one of X ⁶ and X ⁷ is N. In certain embodiments, one of X ⁶ and X ⁷ is N. In certain embodiments, X ⁶ and X ⁷ represent N.

[135] In certain embodiments, R ² is -NR ^2g R ^2h . As described above, each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , -P(O)R ^21b R ^22b , -S (O)R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S(O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl . In certain embodiments, R ^2g is H and R ^2h is D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl.

[136] In certain embodiments, R ² is where X ² represents N or CR ^2a ; X ³ represents N or CR ^2c ; X ⁴ represents N or CR ^2d ; a X ⁵ represents N or CR ^2e .

[137] In certain embodiments, R ² is

[138] In certain embodiments, X ² is CR ^2a . In certain embodiments, X ² is N.

[139] In certain embodiments, R ^2a is H, halogen, C ₁ -C ₆ alkyl, or -COR ^3b . In certain cases, R ^2a is H, fluorine, chlorine, methyl or -COOH.

[140] In certain embodiments, R ² is In certain embodiments, R ² is

[141] In certain embodiments, R ² is

[142] In certain embodiments, X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2d .

[143] In certain embodiments, R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, and -CN. In certain cases, R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently selected from the group consisting of H, halogen and C ₁ -C ₆ alkyls. In certain cases, two of R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are independently selected from the group consisting of H, halogen and C ₁ -C ₆ alkyl. In certain cases, three of R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are independently selected from the group consisting of H, halogen and C ₁ -C ₆ alkyl.

[144] In certain embodiments, R ² is In certain cases, R ^2b and R ^2f are C ₁ -C ₆ alkyl. In certain cases, R ^2d is halogen.

[145] In certain embodiments, R ² is

[146] In certain embodiments, X ³ is N; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2d . In certain embodiments, X ³ is CR ^2c ; X ⁴ represents N; and X ⁵ represents CR ^2d . In certain embodiments, X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents N.

[147] As described above, R ¹ is selected from the group consisting of In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is

[148] In certain embodiments, R ^1w and R ^1y do not approach the atoms to which they are attached to form a 3-7 membered heterocyclyl.

[149] In certain embodiments, R ^1x and R ^1y do not approach the atoms to which they are attached to form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl.

[150] In certain embodiments, R ^1y and the atoms to which it is attached do not approach R ^1x or R ^1w or their attached atoms to form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl.

[151]. In certain embodiments, at least one of R ^1w , R ^1x , and R ^1y is different from H. In certain embodiments, one of R ^1w , R ^1x , and R ^1y is different from H. In certain embodiments, R ^1w , R ^1x , and R ^1y are different from H. In certain embodiments, R ^1w , R ^1x , and R ^1y are H.

[152] In certain embodiments, R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[153] In certain embodiments, R ^1x and R ^1y are each independently H, D, halogen, -CN, -NO ₂ , -SR ^7a , - OR ^7a , -C(O)R ^7b , -P(O )R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , - NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ⁸ a, -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[154] In certain embodiments, R ^1w is H or C ₁ -C ₆ alkyl. In certain embodiments, R ^1x is H or C ₁ -C ₆ alkyl. In certain embodiments, R ^1y is H or C ₁ -C ₆ alkyl.

[155] In certain embodiments, R ^1w and R ^1y, together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl; wherein the 3-7 membered heterocyclyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P (O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a .

[156] In certain embodiments, R ^1w and R ^1y approach the atoms to which they are attached to form a 3-7 membered heterocyclyl, R ^1w and R ^1y being adjacent.

[157] In certain embodiments, R ^1x and R ^1y, together with the atoms to which they are attached, can form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a .

[158] In certain embodiments, R ^1x and R ^1y approach the atoms to which they are attached to form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl, R ^1x and R ^1y being adjacent.

[159] In certain embodiments, R ^1x and R ^1y approach the atoms to which they are attached to form a 5-6 membered heteroaryl, R ^1x and R ^1y are adjacent.

[160] In certain embodiments, R ^1z is H.

[161] As described above, in certain embodiments, R ¹ is selected from the group consisting of

[162] In certain embodiments, R ¹ is In certain embodiments, R ¹ represents is In certain embodiments, R ¹ is

[163] In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is

[164] In certain embodiments, R ¹ is selected from the group consisting of

[165] In certain embodiments, R ¹ is selected from the group consisting of

[166] In certain embodiments, R ¹ is selected from the group consisting of

[167] In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is

[168] In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is In certain embodiments, R ¹ is

[169] In certain embodiments, R ¹ is selected from the group consisting of

[170] In certain embodiments, R ¹ is selected from the group consisting of

[171] In certain embodiments, R ¹ is selected from the group consisting of

[172] In certain embodiments, R ¹ is selected from the group consisting of

[173] In certain embodiments, R ¹ is selected from the group consisting of

[174] In certain embodiments, R ¹ is selected from the group consisting of

[175] In certain embodiments, R ¹ is selected from the group consisting of

[176] In certain embodiments, R ¹ is selected from the group consisting of

[177] In certain embodiments, R ¹ is selected from the group consisting of

[178] In certain embodiments, R ¹ is selected from the group consisting of

[179] In certain embodiments, R ¹ is selected from the group consisting of

[180] In certain embodiments, R ¹ is

[181] In certain embodiments, R ¹ is selected from the group consisting of

[182] In certain embodiments, R ¹ is selected from the group consisting of

[183] In certain embodiments, R ^1a and R ^1b are independently H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O ) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl. In certain embodiments, at least one of R ^1a and R ^1b is different from H. In certain embodiments, one of R ^1a and R ^1b is different from H. In certain embodiments, both R ^1a and R ^1b are different from H. In certain embodiments embodiments R ^1a and R ^1b are H.

[184] In certain embodiments, R ^1c and R ^1d are independently H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O ) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl. In certain embodiments, at least one of R ^1c and R ^1d is different from H. In certain embodiments, one of R ^1c and R ^1d is different from H. In certain embodiments, both R ^1c and R ^1d are different from H. In certain embodiments embodiments R ^1c and R ^1d are H.

[185] In certain embodiments, R ^1e and R ^1f are independently H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O ) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl. In certain embodiments, at least one of R ^1e and R ^1f is different from H. In certain embodiments, one of R ^1e and R ^1f is different from H. In certain embodiments, both R ^1e and R ^1f are different from H. In certain embodiments embodiments R ^1e and R ^1f are H.

[186] In certain embodiments, R ^1g and R ^1h are independently H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O ) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl. In certain embodiments, at least one of R ^1g and R ^1h is different from H. In certain embodiments, one of R ^1g and R ^1h is different from H. In certain embodiments, both R ^1g and R ^1h are different from H. In certain embodiments embodiments R ^1g and R ^1h are H.

[187] The compounds of this invention may contain a basic amino group. It is expected that the inclusion of a basic amino group in a compound of this invention, which may also bear an acidic moiety, will exist as a zwitterion having zero net charge. Zwitterionic compounds may have different physicochemical properties than weak organic acids. It should be noted that an increase in volumes of distribution in vivo may be observed, as well as a decrease in plasma protein binding.

[188] In certain embodiments, at least one of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , and R ^1h is -C(O)R ^11b , -P(O) R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12b , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and –NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -nr ^11a c(o)nr ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen.

[189] In certain embodiments, at least one of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g , and R ^1h is -NR ^11a R ^12a , -NR ^11a C(O) R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a r ^12a , -NR ^11a c(o)r ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen.

[190] In certain embodiments, R ^1a and R ^1b are independently H, -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1a is H, and R ^1b is -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O)R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a , and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)OR ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1a and R ^1b is different from H. In certain embodiments, one of R ^1a and R ^1b is different from H. In certain embodiments, both R ^1a and R ^1b are different from H.

[191] In certain embodiments, R ^1a and R ^1b are independently H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O) NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O )NR ^12a and -NR ^11a S(O) ₂ R ^12a , and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O) R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1a is H, and R ^1b is -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1a and R ^1b is different from H. In certain embodiments, one of R ^1a and R ^1b is different from H. In certain embodiments, both R ^1a and R ^1b are different from H. In certain embodiments embodiments R ^1a and R ^1b are H.

[192] In certain embodiments, R ^1c and R ^1d are independently H, -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12b , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1c is H and R ^1d is -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ - C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1c and R ^1d is different from H. In certain embodiments, one of R ^1c and R ^1d is different from H. In certain embodiments, both R ^1c and R ^1d are different from H.

[193] In certain embodiments, R ^1c and R ^1d are independently H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O) NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a , and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O )R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1c is H and R ^1d is -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a , and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O )R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1c and R ^1d is different from H. In certain embodiments, one of R ^1c and R ^1d is different from H. In certain embodiments, both R ^1c and R ^1d are different from H.

[194] In certain embodiments, R ^1e and R ^1f are independently H, -C(O)R ^11b , -P(O)R ^11b R ^12a , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1e is H, and R ^1f is -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ - C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11b R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , nr ^11a c(o)nr ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1e and R ^1f is different from H. In certain embodiments, one of R ^1e and R ^1f is different from H. In certain embodiments, both R ^1e and R ^1f are different from H.

[195] In certain embodiments, R ^1e and R ^1f are independently H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O) NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1e is H and R ^1f is -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a , and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O )R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1e and R ^1f is different from H. In certain embodiments, one of R ^1e and R ^1f is different from H. In certain embodiments, both R ^1e and R ^1f are different from H.

[196] In certain embodiments, R ^1g and R ^1h are independently H, -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12b , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1g is H and R ^1h is -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12b , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ - C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3 7-membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1g and R ^1h is different from H. In certain embodiments, one of R ^1g and R ^1h is different from H. In certain embodiments, both R ^1g and R ^1h are different from H.

[197] In certain embodiments, R ^1g and R ^1h are independently H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O) NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, R ^1g is H, and R ^1h is -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -nr ^11a c( o)nr ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a . In certain embodiments, the 3-7 membered heterocyclyl contains nitrogen. In certain embodiments, at least one of R ^1g and R ^1h is different from H. In certain embodiments, one of R ^1g and R ^1h is different from H. In certain embodiments, both R ^1g and R ^1h are different from H.

[198] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers, the formula of which is Formula (I) (e.g., Formula (I-1), (I-2) , (I-3), (I-4), (I-5) and (I-6)):

[199] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, the formula of which is formula (Ia):

[200] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, the formula of which is formula (Ib):

[201] In some embodiments, provided herein is a compound of formulas (I), (Ia), or (Ib) having one, two, or three of the following features:

a) R ¹⁰⁰ represents H;

b) R ¹ represents

c) R ² represents

d) X ² represents CH or CF.

[202] In some embodiments, provided herein is a compound of formulas (I), (Ia), or (Ib) having one, two, or three of the following features:

a) R ¹⁰⁰ represents H;

b) R ¹ represents

c) R ² represents

d) X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2d .

[203] Representative compounds are listed in Table 1. It should be understood that the individual enantiomers and diastereomers are included in the table below under compound number and compound name, and their respective structures can be readily determined from them. In some cases, enantiomers or diastereomers are identified by their respective properties, such as retention time on a chiral HPLC column or biological activity, and the absolute stereo configurations of the chiral centers are assigned in an arbitrary order.

[204] In some embodiments, a compound selected from Compounds Nos. 1 to 210 in Table 1, or a salt (eg, a pharmaceutically acceptable salt), solvate (eg, a hydrate), isomer, or tautomer thereof, is provided. In some embodiments, a compound selected from Compounds Nos. 1 to 158 in Table 1, or a salt (eg, a pharmaceutically acceptable salt), solvate (eg, a hydrate), isomer, or tautomer thereof, is provided. In some embodiments, a compound selected from compounds Nos. 159-158 in Table 1, or a salt (eg, a pharmaceutically acceptable salt), solvate (eg, a hydrate), isomer, or tautomer thereof, is provided. In some embodiments, the compound is selected from Compounds Nos. 1 to 158 in Table 1 or is a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), isomer, or tautomer thereof. In some embodiments, the compound is selected from Compounds Nos. 1-39 in Table 1 or is a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), isomer, or tautomer thereof. In some embodiments, the compound is selected from Compounds Nos. 37, 60, 68-69, 72-73, 102-103, and 159-170 in Table 1, or is a salt thereof (e.g., a pharmaceutically acceptable salt), solvate (e.g., a hydrate ), isomer or tautomer. In some embodiments, the compound is selected from compounds No. 171189 in Table 1 or is a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), isomer, or tautomer thereof. In some embodiments, the compound is selected from Compound Nos. 190202 in Table 1 or is a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), isomer, or tautomer thereof. In some embodiments, the compound is selected from compounds Nos. 203-210 in Table 1 or is a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), isomer, or tautomer thereof.

[205] In certain embodiments, provided herein is a compound and its pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, and tautomers that is selected from the group consisting of

[206] In certain embodiments, provided herein is a compound and its pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, and tautomers that is selected from the group consisting of

[207] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers and tautomers, which is selected from the group consisting of

[208] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers and tautomers, which is selected from the group consisting of

[209] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers and tautomers, which is selected from the group consisting of

[210] Provided herein is a compound and its pharmaceutically acceptable salts, solvates (eg, hydrates), isomers and tautomers, which is selected from the group consisting of

Methods for synthesizing compounds

[211] The compounds of this description can be prepared using a number of methods, including standard chemistry. Suitable synthesis methods are illustrated in the schemes provided herein.

[212] The compounds described herein can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes. It should be understood that in the schemes described herein for sensitive or reactive groups, protecting groups are applied as necessary in accordance with general principles or chemistry. Work with protecting groups is carried out in accordance with standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compound using methods known to those skilled in the art. The selection process, as well as the reaction conditions and procedure, must be consistent with the preparation of the compounds described in this document.

[213] Those skilled in the art will appreciate whether a stereocenter exists in the compounds described herein. In some embodiments, the compounds of the invention may exist as enantiomeric or diastereomeric stereoisomers. Accordingly, this invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be prepared by stereospecific synthesis or by resolution of the final product or any convenient intermediate. For example, enantiomerically pure compounds of the invention can be prepared using enantiomerically pure chiral building blocks. Alternatively, racemic mixtures of the final compounds or a racemic mixture of a near-terminal intermediate can be subjected to chiral purification as described herein to provide the desired enantiomerically pure intermediates or final compounds. When a near-final intermediate is purified into its individual enantiomers, each individual enantiomer can be processed separately to provide the desired final enantiomerically pure compounds of the invention. Resolution of the final product, intermediate product or starting material can be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds," by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[214] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic processes.

Receiving connections

[215] As an example, the compounds of this invention can be synthesized by following the steps shown in General Schemes 1 and 2, which contain examples of the sequence for preparing the compounds of the invention. Starting materials are commercially available or prepared using known procedures described in the literature or illustrated. Preferred methods include, but are not limited to, the methods described herein.

General scheme 1

[216] Formula I (compound F) can be prepared according to the general procedures given in General Scheme 1. In General Scheme 1, PG ^G1 is a protecting group. The sulfonamide (A) is provided with a protecting group to obtain the protected sulfonamide (B). The protected sulfonamide (B) is converted to the protected sulfonimide (C) by activation (ie, deoxychlorination or catalysis) and treatment with a reaction mixture with a source of ammonia (or amine to produce R ¹⁰⁰ - not shown). The protected sulfonimidamide (C) is reacted with isocyanate (D) to obtain compound (E). Connection (E) is then deprotected to obtain connection (F).

General scheme 2

[217] Formula I (Compound L) can also be prepared according to the general procedures given in General Scheme 2. In General Scheme 2, PG ^G2 is a protecting group and LG ¹ is a leaving group (typically a halogen that can be activated as a reactive particle, i.e. via lithium-halogen exchange). Reaction of compound (G) and compound (H), followed by activation and treatment with a source of ammonium (illustrated) or primary amine (not illustrated for substituted NR ¹⁰⁰ ) gives the protected sulfonimidamide (I). Connection (K) is then deprotected to obtain connection (L).

[218] General Scheme 3 shows a typical synthesis of the R ¹ fragment.

General scheme 3

[219] General Scheme 3 shows the preparation of compound (R) or a salt or solvate thereof. In the general scheme, 3 X ¹ represents a halogen (e.g., chlorine, bromine, iodine, or fluorine), sulfonate (e.g., nosylate, tosylate, or mesylate), nitrate, phosphate, or other suitable leaving group, and PG ^N1 represents an amino protecting group .

[220] Compound (M) is provided with a protecting group to produce compound (N). Thereafter, compound (N) is alkylated to form compound (O), for example, using the Mitsunobu reaction. Compound (O) is deprotected and cyclized to form compound (P). Compound (P) is then reacted with a sulfonating reagent to form compound (Q). Compound (Q) is then activated (ie by chlorination) and then reacted with an ammonia source to form compound (R). Alternatively, compound (P) can be brominated to produce starting materials, such as compound (G) in General Scheme 2.

General scheme 4

[221] Formula I (Compound X) can be prepared according to the general procedures outlined in General Scheme 4. Sulfonyl chloride (S) is converted to sulfinic acid methyl ester (T) by reduction followed by formation of sulfinyl chloride and subsequent esterification. Sulfinic acid methyl ester (T) is converted to sulfinamide (U) by reaction with an amine source (such as LiHMDS) followed by hydrolysis. React sulfinamide (U) with isocyanate (V) to obtain compound (V). Compound (W) is then converted to sulfonimidamide (X) by oxidative chlorination followed by reaction with a source of amine or ammonia.

Pharmaceutical compositions

[222] The described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers can be used as such, but are generally administered in the form of a pharmaceutical composition in which one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers (active ingredient) are mixed with a pharmaceutically acceptable adjuvant or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," M. E. Aulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety. In certain embodiments, the compound or its pharmaceutically acceptable salts, isomers, prodrugs, and tautomers are in the form of a hydrate.

[223] Depending on the mode of administration, the pharmaceutical composition contains from about 0.05 to about 99 wt. % (mass percent), more specifically, from about 0.05 to about 80 mass. %, even more specifically, from about 0.10 to about 70 wt. %, and more specifically, from about 0.10 to about 50 wt. % of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, all weight percentages being based on the total weight of the composition.

[224] Provided herein is a pharmaceutical composition containing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers as defined above, admixed with a pharmaceutically acceptable carrier.

[225] Further provided herein is a method of making a pharmaceutical composition of this invention that contains one or more of the described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers as defined above with a pharmaceutically acceptable adjuvant or carrier. The pharmaceutical compositions of the invention can also be prepared according to traditional mixing, granulating or coating methods.

[226] The pharmaceutical compositions of this invention may contain a therapeutically effective amount of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, admixed with one or more pharmaceutically acceptable carriers. Some examples of materials that may serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as coconut oil and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethanol; and phosphate-buffered saline solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants, which may also be present in pharmaceutical compositions at the discretion of the compiler.

[227] Depending on the intended mode of administration, the described pharmaceutical compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injections, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders , liquids, suspensions, etc., sometimes in unit dosages and in accordance with traditional pharmaceutical practice. These regimens may include systemic or local administration, such as oral, nasal, parenteral (eg, by intravenous (both bolus and infusion), intramuscular, or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical (eg, by powders, ointments or drops) modes of administration. These regimens may also include intracisternal, intraperitoneal, oral or nasal spray, or as a liquid aerosol or dry powder pharmaceutical composition for inhalation. In some embodiments, a pharmaceutical composition of the invention containing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers is for oral administration. In some embodiments, a pharmaceutical composition of the invention containing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers is for intravenous administration.

[228] Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, one or more of the described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers may be admixed with at least one inert pharmaceutically acceptable excipient or carrier, such as diluents, excipients or extenders, binders, humectants, disintegrants, solution retarders, absorption accelerators, wetting agents, absorbents, lubricants, emulsifying or dispersing agents and/or agents that enhance the absorption of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg , hydrates), isomers, prodrugs and tautomers. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[229] Solid pharmaceutical compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[230] Solid dosage forms of tablets, dragees, capsules, pills and granules can be formulated with coatings and coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifiers and may also be of a composition capable of releasing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers exclusively or preferentially at a specific site in the gastrointestinal tract, optionally, in a slow manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

[231] One or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers may also be in microencapsulated form with one or more excipients specified herein. Solid dosage forms of tablets, dragees, capsules, pills and granules can be formulated with coatings and coatings, such as enteric coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, one or more of the disclosed compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain, in accordance with common practice, additional substances other than inert diluents, for example, tabletting lubricants or other tabletting additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifiers and may also be of a composition capable of releasing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers exclusively or preferentially at a specific site in the gastrointestinal tract, optionally, in a slow manner. Examples of encapsulating compositions that can be used may include polymeric substances and waxes.

[232] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents , solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, wheat germ, olive , castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitol fatty acid esters and mixtures thereof. In addition to inert diluents, oral pharmaceutical compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners and flavoring agents.

[233] Injectable pharmaceutical compositions, for example, sterile injectable aqueous or oleaginous suspensions, containing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, can be formulated in accordance with the prior art using suitable dispersing or wetting agents and suspending agents. The sterile injectable pharmaceutical composition may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally available diluent or solvent, for example, a solution of 1,3-butanediol. Acceptable vehicles that may be used include water, Ringer's solution, USP 1% lidocaine, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are traditionally used as a solvent or suspending medium. For these purposes, any light, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the injectable composition.

[234] Injectable pharmaceutical compositions can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injection medium prior to use.

[235] To prolong the effect of one or more described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers, it may be necessary to slow the absorption of one or more described compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates ), isomers, prodrugs and tautomers after subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers depends on the dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers can be achieved by dissolving or suspending one or more of the described compounds and their pharmaceutically acceptable salts, solvates ( e.g. hydrates), isomers, prodrugs and tautomers in the carrier oil. Injectable depot forms are prepared by forming microencapsulated matrices of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of one or more described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers and polymer, as well as the nature of the particular polymer used, the rate of release of one or more described compounds and their pharmaceutical acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable pharmaceutical depot compositions can also be prepared by enclosing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers in liposomes or microemulsions compatible with body tissues.

[236] Pharmaceutical compositions for rectal or vaginal administration can be suppositories, which can be prepared by mixing one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers with suitable non-irritating excipients substances or carriers, such as coconut oil, polyethylene glycol or suppository wax, which are solid at ambient temperature and liquid at body temperature and therefore melt in the rectal or vaginal cavity to release one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg hydrates), isomers, prodrugs and tautomers.

[237] One or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers can also be prepared in suppository form, which can be prepared from fatty emulsions or suspensions using polyalkylene glycols such as propylene glycol , as a carrier.

[238] Dosage forms for topical or transdermal administration of one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers include ointments, pastes, creams, lotions, gels, powders, solutions, sprays , inhalers or patches. One or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers are mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as needed. Ophthalmic pharmaceutical compositions, ear drops, etc. are also within the scope of this invention.

[239] Ointments, pastes, creams and gels may contain, in addition to one or more of the described compounds and their pharmaceutically acceptable salts, solvates (for example, hydrates), isomers, prodrugs and tautomers, excipients such as fats of animal and vegetable origin, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

[240] One or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers can also be prepared for use as topical powders and sprays, which may contain, in addition to one or more of the described compounds and their pharmaceutically acceptable salts, solvates (eg hydrates), isomers, prodrugs and tautomers, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons.

[241] An additional advantage of transdermal patches is that they provide controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of one or more of the disclosed compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers through the skin. The rate can be controlled by a rate control membrane or by dispersing one or more of the disclosed compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers in a polymer matrix or gel.

[242] The pharmaceutical compositions of the invention can also be formulated for delivery as a liquid aerosol or an inhalable dry powder. Liquid aerosol pharmaceutical compositions can be aerosolized advantageously to particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder pharmaceutical compositions can be delivered through the endobronchial tree into the terminal bronchioles and ultimately into parenchymal tissue.

[243] Aerosol pharmaceutical compositions of the invention can be delivered using an aerosol generating device, such as a jet, vibrating porous plate or ultrasonic nebulizer, selected to provide the formation of aerosol particles having an average diameter of preferably from 1 to 5 μm. In addition, the pharmaceutical composition may have balanced osmolarity, ionic strength and chloride concentration, and the smallest aerosol volume possible to deliver an effective dose of one or more of the disclosed compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers. In addition, aerosolized pharmaceutical compositions may not adversely affect the functionality of the respiratory tract and may not cause undesirable side effects.

[244] Aerosol devices suitable for administering the aerosol pharmaceutical compositions of the invention include, for example, vibrating porous plate jets, ultrasonic nebulizers, and power-operated dry powder inhalers, which can atomize the pharmaceutical composition of the invention into aerosol particles of predominantly range 15 µm. "Mainly" in the context of this application means that at least 70%, but not necessarily more than 90% of all aerosol particles generated are in the range of 1-5 microns. A jet nebulizer works by using air pressure to spray a liquid solution into aerosol droplets. Vibrating porous plate nebulizers operate by using a sonic vacuum provided by a rapidly vibrating porous plate to force a solution through the porous plate. An ultrasonic nebulizer operates using a piezoelectric crystal that crushes liquid into small aerosol droplets. A number of suitable devices are available, including, for example, AeroNeb and AeroDose vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.), Sidestream7 nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC7 jet nebulizers, and Pari LC Star7 (Pari Respiratory Equipment, Inc., Richmond, Va.) and aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and ultrasonic μLtraAire7 (Omron Healthcare, Inc., Vernon Hills, Ill.) nebulizers.

Methods of application

[245] The described compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, and compositions can be used as pharmaceuticals, as discussed herein.

[246] Provided herein are methods of treating a disorder, comprising the step of administering an effective amount of one or more compounds herein and pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers thereof, thereby treating the disorder in a subject in need. in this subject.

[247] Provided herein are methods of treating a disorder, comprising the step of administering an effective amount of one or more pharmaceutical compositions herein to thereby treat the disorder in a subject in need thereof.

[248] Provided herein are one or more compounds described herein and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers, or one or more pharmaceutical compositions described herein, for use in treating a disorder in a person in need of this subject.

[249] Provided herein is the use of one or more compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers for treating a disorder in a subject in need thereof. Provided herein is the use of one or more compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers for the treatment of a disorder in a subject in need thereof, wherein the disorder is responsive to inflammasome inhibition.

[250] Provided herein is the use of one or more compositions described herein for treating a disorder in a subject in need thereof. Also provided herein is the use of one or more compositions herein for treating a disorder in a subject in need thereof, wherein the disorder is susceptible to inflammasome inhibition.

[251] Provided herein is the use of one or more compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers in the manufacture of a medicament for treating a disorder. Provided herein is the use of one or more compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers in the manufacture of a medicament for the treatment of a disorder that is susceptible to inflammasome inhibition.

[252] Proposed herein is the use of one or more compositions herein in the manufacture of a medicament for treating a disorder. This specification provides the use of one or more of the compositions disclosed herein in the manufacture of a medicament for the treatment of a disorder that is susceptible to inflammasome inhibition.

[253] Provided herein is the use of one or more compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers as a drug for the treatment of a disorder.

[254] Provided herein is the use of one or more compositions herein as a medicament for the treatment of a disorder.

[255] In some embodiments, the disorder is a disorder that is susceptible to inhibition of inflammasome activation. In some embodiments, the disorder is a disorder that is susceptible to inhibition of NLRP3 inflammasome activation.

[256] In some embodiments, one or more of the compounds herein and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers, or pharmaceutical compositions herein are useful as a specific NLRP3 inhibitor.

[257] In some embodiments, the disorder is susceptible to modulation by one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells . In some embodiments, the disorder is susceptible to modulation of one or more of IL-1β and IL-18.

[258] In some embodiments, the modulation is the inhibition of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, and IL-33. In some embodiments, the modulation is inhibition of one or more of IL-1β and IL-18.

[259] In some embodiments, modulation of Th17 cells occurs by inhibiting the production and/or secretion of IL-17.

[260] In some embodiments, the disorder is a disorder of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, urinary system, respiratory system, central nervous system, cancer or other malignancy, and/ or caused by or associated with a pathogen.

[261] It should be understood that the general embodiments defined in accordance with the broad categories of disorders are not mutually exclusive. In this regard, any specific violation can be categorized in accordance with more than one of the general embodiments described herein. A non-limiting example is type I diabetes mellitus, which is an autoimmune disease and a disease of the endocrine system.

[262] In some embodiments, the disorder is a disorder of the immune system. In some embodiments, the disorder is an inflammatory disorder or an autoimmune disorder.

[263] In some embodiments, the disorder is a liver disorder.

[264] In some embodiments, the disorder is a pulmonary disorder.

[265] In some embodiments, the disorder is a skin disorder.

[266] In some embodiments, the disorder is a cardiovascular disorder.

[267] In some embodiments, the disorder is a cancer, tumor, or other malignancy. As used herein, cancers, tumors and malignancies refer to disorders, or cells or tissues associated with disorders, that are characterized by aberrant or abnormal cellular proliferation, differentiation and/or migration, often accompanied by an aberrant or abnormal molecular phenotype, which includes one or more genetic mutations or other genetic changes associated with tumorigenesis, expression of tumor markers, loss of expression or tumor suppression activity, and/or aberrant or abnormal expression of cell surface markers. In some embodiments, cancers, tumors, and malignancies may include, but are not limited to, sarcomas, lymphomas, leukemias, solid tumors, blastomas, gliomas, carcinomas, melanomas, and metastatic cancers. A more comprehensive list of cancers, tumors, and malignancies can be found on the National Cancer Institute web page at http://www.cancer.gov/cancertopics/types/alphalist, which is incorporated herein by reference in its entirety.

[268] In some embodiments, the disorder is a urinary tract disorder.

[269] In some embodiments, the disorder is a gastrointestinal disorder.

[270] In some embodiments, the disorder is a respiratory system disorder.

[271] In some embodiments, the disorder is an endocrine system disorder.

[272] In some embodiments, the disorder is a central nervous system (CNS) disorder.

[273] In some embodiments, the disorder is caused by or related to a pathogen. The pathogen may be, but is not limited to, a virus, bacterium, protozoan, worm or fungus, or any other organism capable of infecting a mammal.

[274] Non-limiting examples of viruses include, but are not limited to, influenza virus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), alphavirus such as Chikungunya and Ross River virus, flaviviruses such as Dengue virus, Zika virus and papillomavirus them.

[275] Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteureiia multicida, gella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typ hi, Borrelia burgdorferi and Yersinia pestis , although not limited to them.

[276] Non-limiting examples of protozoa include, but are not limited to, Plasmodium, Babesia, Giardia, Entamoeba, Leishmania and Trypanosomes.

[277] Non-limiting examples of worms include, but are not limited to, helminths, including schistosomes, roundworms, tapeworms, and flukes.

[278] Non-limiting examples of fungi include, but are not limited to, Candida and Aspergillus species.

[279] In some embodiments, the disorder is selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndrome (CAPS): Muckle-Wels syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease age (NOMID); autoinflammatory disease: familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majeed syndrome, suppurative arthritis , pyoderma and acne gangrenosum (PAPA), haploinsufficiency A20 (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD); Sweet's syndrome; chronic nonbacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune disease, including multiple sclerosis (MS), type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Behçet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria and brain damage due to pneumococcal meningitis; metabolic disease, including type 2 diabetes mellitus, atherosclerosis, obesity, gout and pseudogout; eye diseases, including ocular epithelial diseases, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye syndrome; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reaction of the skin, including contact hypersensitivity and sunburn; inflammatory response in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease and relapsing polychondritis; viral infection, including alphavirus infection (Chikungunya, Ross River), flavivirus infection (Dengue and Zika virus), influenza and HIV; hidradenitis suppurativa (HS) and other cystic skin diseases; oncological diseases, including metastases of lung cancer, pancreatic malignancy, gastric malignancy, myelodysplastic syndrome and leukemia; polymyositis; stroke; myocardial infarction; graft versus host disease; hypertension; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome; ischemia-reperfusion injury and any disease in which the individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[280] In some embodiments, the disorder is cryopyrin-associated periodic syndrome (CAPS).

[281] In some embodiments, the disorder is atherosclerosis.

[282] In one non-limiting example described, the disorder being treated is NASH. Activation of the NLRP3 inflammasome is key for inflammatory recruitment in NASH, and inhibition of NLRP3 can both prevent and reverse liver fibrosis. One or more of the compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers or pharmaceutical compositions thereof of this invention, through disruption of NLRP3 inflammasome function in liver tissue, may result in histological reduction in liver inflammation, reduction in macrophage recruitment and neutrophils and suppression of NF-κB activation. Inhibition of NLRP3 can reduce the expression of pro-IL-1β in the liver and normalize the levels of IL-1β, IL-6 and MCP-1 in the liver and circulation, thereby helping in the treatment of the disorder.

[283] In a further non-limiting example described, the disorder being treated is severe steroid-resistant asthma (SSR). Respiratory tract infections induce the NLRP3/caspase-1/IL-1β inflammasome signaling axis in the lungs, which promotes the development of SSR asthma. The NLRP3 inflammasome recruits and activates procaspase-1 to induce IL-1β responses. NLRP3 inflammasome-induced IL-β responses are therefore important for infection control, however, excessive activation leads to aberrant inflammation and has been linked to the pathogenesis of asthma SSR and COPD. Administration of one or more compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers or pharmaceutical compositions thereof of this invention that target specific disease processes is more therapeutically attractive than nonspecific inhibition of inflammatory responses by steroids or ILs -1β. Therefore, targeting the NLRP3/caspase-1/IL-1β inflammasome signaling axis of one or more compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers or pharmaceutical compositions of the present invention may be advantageous in the treatment of bronchial asthma SSR and other steroid-resistant inflammatory conditions.

[284] In one further non-limiting example described, the disorder being treated is Parkinson's disease. Parkinson's disease is the most common neurodegenerative movement disorder and is characterized by selective loss of dopaminergic neurons accompanied by the accumulation of misfolded α-synuclein (Syn) Lewy bodies, which are the pathological hallmarks of the disease. Chronic microglial neuroinflammation is evident early in the disease and has been suggested to mediate the pathology.

[285] Microglial NLRP3 appears to play a key role in the progression of Parkinson's disease. The NLRP3 inflammasome is activated by fibrillar Syn through a Syk kinase-dependent mechanism and is also observed in the absence of Syn pathology in the early stages of dopaminergic degeneration and mediates neuronal loss. One or more of the compounds or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs and tautomers or pharmaceutical compositions thereof of this invention may block NLRP3 inflammasome activation by fibrillary Syn or mitochondrial dysfunction and thereby provide effective neuroprotection of the nigrostriatal dopaminergic system and help treat Parkinson's disease.

[286] In some embodiments, the method treats a disorder, including, but not limited to, bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis , liver disease, liver fibrosis, hepatic steatosis, fatty liver disease, gout, lupus, lupus nephritis, Crohn's disease, IBD (inflammatory bowel disease), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[287] In certain embodiments, the disorder is selected from the group consisting of NASH (non-alcoholic steatohepatitis); myelodysplastic syndrome (MDS); myeloproliferative neoplasm (MPN); CAPS (cryopyrin-associated periodic syndromes); IPF (idiopathic pulmonary fibrosis); MI (R/I) (myocardial infarction and reperfusion injury); gout; I/O (immuno-oncology); bronchial asthma; IBD (inflammatory bowel disease); kidney fibrosis; Still's disease with onset in adulthood; systemic juvenile idiopathic arthritis; tumor necrosis factor receptor-associated periodic syndrome (TRAPS); colchicine-resistant familial Mediterranean fever (FMF); hyper-IgD syndrome (HIDS)/mevalonate kinase deficiency (MKD); traumatic brain injury; Parkinson's disease; moderate to severe inflammatory acne; acute non-anterior non-infectious uveitis (NIU); AD (Alzheimer's disease); COPD (chronic obstructive pulmonary disease); sepsis; MS (multiple sclerosis); Behçet's disease; Crohn's disease; RA (rheumatoid arthritis); erosive osteoarthritis; T1D (type 1 diabetes mellitus); T2D (type 2 diabetes mellitus); obesity; osteoporosis; cystic fibrosis; alcoholic liver disease; aging; HCC (hepatocellular carcinoma); depression; endometriosis; pyoderma gangrenosum (“PG”), a rare skin ulcer; lupus, lupus nephritis; epilepsy; ischemic stroke; deafness; sickle cell anemia; SLE (systemic lupus erythematosus); and spinal cord damage.

[288] In some embodiments, the disorder is selected from the group consisting of lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, and inflammatory bowel disease (IBD).

[289] In some embodiments, the disorder is gout.

[290] In some embodiments, the disorder is lupus.

[291] In some embodiments, the disorder is lupus nephritis.

[292] In some embodiments, the disorder is Crohn's disease.

[293] In some embodiments, the disorder is IBD (inflammatory bowel disease).

[294] In some embodiments, the disorder is MDS (myelodysplastic syndromes).

[295] In some embodiments, the disorder is MPN (myeloproliferative neoplasms).

[296] In the case of therapeutic applications mentioned herein, the dose administered will, of course, vary depending on the one or more compounds used and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions, regimen administration, required treatment and identified disorder. For example, the daily dosage of one or more of the compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers herein, when inhaled, may range from about 0.05 micrograms per kilogram of body weight ( mcg/kg) to about 100 micrograms per kilogram of body weight (mcg/kg). Alternatively, if one or more compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs, and tautomers are administered orally, the daily dosage of one or more compounds herein may range from about 0.01 microgram per kilogram of body weight (mcg/kg) to about 100 milligrams per kilogram of body weight (mg/kg).

[297] It should be understood that the decision regarding the total daily intake of one or more compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers, as well as pharmaceutical compositions herein rests with the attending physician with medical knowledge. points of view. The specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific pharmaceutical composition used; age, body weight, general health, gender, diet of the patient; timing of administration, route of administration, and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or with the specific compound used; and similar factors well known in the medical field. A physician or veterinarian skilled in the art can readily determine and prescribe the therapeutically effective amount of one or more compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions described herein required for treatment , counteracting or stopping the progression of the disorder.

Combination therapy

[298] In some embodiments, one or more of the compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions described herein can be used alone or administered together or used in combination with a known therapeutic agent or pharmaceutical composition. Co-administration or use in combination can refer to any form of administration of two or more different compounds or pharmaceutical compositions so as to administer the second compound or second pharmaceutical composition while the first compound or first pharmaceutical composition is still effective in the body. For example, different compounds or pharmaceutical compositions can be administered in the same formulation or in separate formulations, simultaneously, sequentially, or by administering separate doses of individual treatment components. In some embodiments, different compounds or pharmaceutical compositions may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week relative to each other. Thus, an individual who receives such treatment may achieve a positive result due to the combined effect of different compounds or pharmaceutical compositions.

[299] In some embodiments, one or more compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions as described are used in combination with one or more other compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions as described in the methods or uses as described. In certain such embodiments, a combination of one or more compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions as described are used in a method of treating one or more disorders listed herein.

[300] In some embodiments, combinations of one or more compounds and their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers or pharmaceutical compositions provided herein, or combinations of other known agents or pharmaceutical compositions and one or more of the compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions provided herein are mixed into pharmaceutical compositions and drugs that are useful in the methods and applications herein. This disclosure also provides for the use of such combinations in the treatment of one or more of the disorders listed herein.

[301] In some embodiments, one or more compounds and their pharmaceutically acceptable salts, solvates (eg, hydrates), isomers, prodrugs and tautomers or pharmaceutical compositions as described herein are administered at a subtherapeutic dose, wherein the subtherapeutic dose is the dose that was would not be sufficient to treat one or more of the disorders listed herein when administered separately.

Illustrative Embodiments of the Invention

[302] Some embodiments of this invention are Embodiments I below:

[303] Embodiment I-1. A compound having the structure of formula (I)

or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein

R ¹⁰⁰ is selected from the group consisting of H, Cl, D, -CN, -NO ₂ , -OR ^3a , -C(O)R ^3b , -S(O) ₂ R ^3b , -S(O)R ^3b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6- heteroaryl member; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^3a , -C(O)R ^3b , -P(O)R ^3b R ^4b , -S(O) ₂ R ^3b , -S(O)R ^3b , -NR ^3a R ^4a , -NR ^3a C(O)R ^4a ,

-NR ^3a C(O)OR ^4a , -NR ^3a C(O)NR ^4a , -NR ^3a S(O) ₂ R ^4a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 -6-membered heteroaryl;

R ¹ is selected from the group consisting of

where R ^1w is selected from the group consisting of H, D, -CN, -C(O)R ^5b , -S(O) ₂ R ^5b , -S(O)R ^5b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^5a , -C(O)R ^5b , -P(O)R ^5b R ^6b , -S(O) ₂ R ^5b , -S(O)R ^5b , -NR ^5a R ^6a , -NR ^5a C(O)R ^6a , -NR ^5a C(O)OR ^6a , -NR ^5a C(O)NR ^6a , -NR ^5a S(O) ₂ R ^6a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

each R ^1x and R ^1y independently represents H, D, halogen, -CN, NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S( O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

where R ^1w and R ^1y , together with the atoms to which they are attached, can form a 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7 membered heterocyclyl and the 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C( O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ; or

where R ^1x and R ^1y together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl or 5-6-membered aryl or heteroaryl; where C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^9a , -C(O)R ^9b , -P(O)R ^9b R ^10b , -S(O) ₂ R ^9b , -S(O)R ^9b , -NR ^9a R ^10a , -NR ^9a C(O)R ^10a , -NR ^9a C(O)OR ^10a , -NR ^9a C(O)NR ^10a and -NR ^9a S(O) ₂ R ^10a ;

R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C ₆ aryl and -NR ^2g R ^2h ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl and C ₆ aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D , -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O )NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ¹⁰ cycloalkyl, C ³ -C ¹⁰ cycloalkyl, C ⁶ aryl, 3-7-membered heterocyclyl and 5- 6-membered heteroaryl;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S (O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^21a R ^22a , R ^23a and R ^24a are each independently H, D, C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ² , C ₃ -C ₁₀ cyclalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^21b , R ^22b , R ^23b and R ^24b are each independently H, D, -OH, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[304] Embodiment I-2. The compound of Embodiment I-1 or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5 -membered heteroaryl, -NR ^2g R ^2h , ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S (O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ₆ and X ⁷ represents N;

R ^2a represents H, D, halogen, -CN, OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5 6- heteroaryl members are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O ) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , - NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S (O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^15a , R ^16a , R ^17a , R ^18a , R ^19a , R ^20a and R ^21a are in each case independently H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl , C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl; R ^15b , R ^17b , R ^18b and R ^21b are in each case independently H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl.

[305] Embodiment I-3. The compound of any one of embodiments I-1 to I-2, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is or

[306] Embodiment I-4. The compound of Embodiment I-1, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

R ^1z represents H, D, halogen, -CN, -NO ₂ , -SR ^7a , -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S (O) ₂ R ^8a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7- membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^7a , -C(O)R ^7b , -P(O)R ^7b R ^8b , -S(O) ₂ R ^7b , -S(O)R ^7b , -NR ^7a R ^8a , -NR ^7a C(O)R ^8a , -NR ^7a C(O)OR ^8a , -NR ^7a C(O)NR ^8a , -NR ^7a S(O) ₂ R ^8a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from H, D, halogen, -CN, -NO ₂ , -SR ^11a , -OR ^11a , -C (O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , - NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl or 5-6-membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , if present, together with the atoms to which they are attached, can form a C ₃ -C ₁₀ cycloalkyl or 3-7-membered heterocyclyl; where C ₃ -C ₁₀ cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ^13a , -C( O)R ^13b , -P(O)R ^13b R ^14b , -S(O) ₂ R ^13b , -S(O)R ^13b , -NR ^13a R ^14a , -NR ^13a C(O)R ^14a , -NR ^13a C(O)OR ^14a , -NR ^13a C(O)NR ^14a and -NR ^13a S(O) ₂ R ^14a ; or

two geminal groups R ^1a and R ^1b ; R ^1c and R ^1d ; R ^1e and R ^1f ; or R ^1g and R ^1h , if present, may form an oxo group;

R ^7a , R ^8a , R ^11a , R ^12a , R ^13a and R ^14a are in each case independently H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^7b , R ^8b , R ^11b , R ^12b , R ^13b and R ^14b independently in each case represent H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[307] Embodiment I-5. The compound of Embodiment I-4, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7 membered heterocyclyl, 5 -membered heteroaryl, -NR ^2g R ^2h , ; where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-7-membered heterocyclyl and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^23a , -C(O)R ^23b , -P(O)R ^23b R ^24b , -S(O) ₂ R ^23b , -S(O)R ^23b , -NR ^23a , R ^24a , -NR ^23a C(O)R ^24a , -NR ^23a C(O)OR ^24a , -NR ^23a C(O)NR ^24a , -NR ^23a S(O) ₂ R ^24a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

X ² represents N or CR ^2a ;

X ³ represents N or CR ^2c ;

X ⁴ represents N or CR ^2d ;

X ⁵ represents N or CR ^2e ;

X ⁶ and X ⁷ are independently N or CR ²ⁿ ; where at least one of X ⁶ and X ⁷ represents N;

R ^2a represents H, D, halogen, -CN, -OR ^15a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -C(O)NR ^15a R ^16a , -C(O)OR ^15a ; -NR ^15a R ^16a , -NR ^15a C(O)R ^16a , -NR ^15a C(O)OR ^16a , -NR ^15a C(O)NR ^16a or -NR ^15a S(O) ₂ R ^16a , where C ₁ -C ₆ alkyl and C ₃ -C ₁₀ cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR ^15a , -C(O)R ^15b , -NR ^15a R ^16a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P( O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2b , R ^2c , R ^2d , R ^2e and R ^2f together with the atoms to which they are attached can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3 7-membered heterocyclyl, 5-6-membered heteroaryl , where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2j , R ^2k , R ^2m and R ²ⁿ independently represents H, D, halogen, -CN, -NO ₂ , -SR ^17a , -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S(O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR ^17a , -C(O)R ^17b , -P(O)R ^17b R ^18b , -S( O) ₂ R ^17b , -S(O)R ^17b , -NR ^17a R ^18a , -NR ^17a C(O)R ^18a , -NR ^17a C(O)OR ^18a , -NR ^17a C(O)NR ^18a , -NR ^17a S(O) ₂ R ^18a , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; or

two adjacent R ^2j , R ^2k , R ^2m and R ²ⁿ , together with the atoms to which they are attached, can form C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, where C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 member heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, C ₁ -C ₆ alkyl, -OR ^19a and NR ^19a R ^20a ;

each R ^2g and R ^2h independently represents H, D, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, oxo, -OR ^21a , -C(O)R ^21b , P(O)R ^21b R ^22b , -S(O) ₂ R ^21b , -S(O)R ^21b , -NR ^21a R ^22a , -NR ^21a C(O)R ^22a , -NR ^21a C(O)OR ^22a , -NR ^21a C(O)NR ^22a , -NR ^21a S (O) ₂ R ^22a , -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^15a , R ^16a , R ^17a , R ^18a , R ^19a , R ^20a and R ^21a are in each case independently H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl , C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

R ^15b , R ^17b , R ^18b and R ^21b are in each case independently H, D, -OH, -O(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NHS(O) ₂ CH ₃ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₆ aryl, 3-7-membered heterocyclyl and 5-6 -membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , - NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.

[308] Embodiment I-6. The compound of Embodiment I-4 or I-5, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is or

[309] Embodiment I-7. The compound of any one of embodiments I-1 to I-6, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹⁰⁰ is H.

[310] Embodiment I-8. The compound of any one of embodiments I-1 to I-7, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is .

[311] Embodiment I-9. The compound of any one of embodiments I-1 to I-8, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein X ² is CR ^2a .

[312] Embodiment I-10. The compound of any one of embodiments I-1 to I-8, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein ^X2 is N.

[313] Embodiment I-11. The compound of any one of embodiments I-1 to I-9, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^2a is H, halogen, C ₁ -C ₆ alkyl, or -C(O)R ^3b .

[314] Embodiment I-12. The compound of any one of embodiments I-1 to I-9, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^2a is H, fluorine, chlorine, methyl, or -COOH.

[315] Embodiment I-13. The compound of any one of embodiments I-1 to I-9 and I-11 to I-12, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is

[316] Embodiment I-14. The compound of any one of embodiments I-1 to I-9 and I-11 to I-12, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is .

[317] Embodiment I-15. The compound of any one of embodiments I-1 to I-7, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is

[318] Embodiment I-16. The compound of Embodiment I-15, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2d .

[319] Embodiment I-17. The compound of any one of embodiments I-15 to I-16, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein each of ^R2b , ^R2c , ^R2d , ^R2e , and ^R2f is independently selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl and -CN.

[320] Embodiment I-18. The compound of any one of embodiments I-15 to I-17, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ² is

[321] Embodiment I-19. The compound of any one of embodiments I-15 to I-18, or pharmaceutically acceptable formulations thereof

salt, solvate, isomer or tautomer, where R ² represents

[322] Embodiment I-20. The compound of Embodiment I-15, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein X ³ is N; X ⁴ represents CR ^2d ; and X ⁵ represents CR ^2d .

[323] Embodiment I-21. The compound of Embodiment I-15, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein X ³ is CR ^2c ; X ⁴ represents N; and X ⁵ represents CR ^2d .

[324] Embodiment I-22. The compound of Embodiment I-15, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein X ³ is CR ^2c ; X ⁴ represents CR ^2d ; and X ⁵ represents N.

[325] Embodiment I-23. The compound of any one of embodiments I-1 to I-22, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[326] Embodiment I-24. The compound of any one of embodiments I-1 to I-22, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[327] Embodiment I-25. The compound of any one of embodiments I-1 to I-22, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[328] Embodiment I-26. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[329] Embodiment I-27. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[330] Embodiment I-28. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[331] Embodiment I-29. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is

[332] Embodiment I-30. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[333] Embodiment I-31. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[334] Embodiment I-32. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[335] Embodiment I-33. The compound of any one of embodiments I-1 to I-32, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1z is H.

[336] Embodiment I-34. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[337] Embodiment I-35. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[338] Embodiment I-36. The compound of any one of embodiments I-1 to I-23, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[339] Embodiment I-37. The compound of any one of embodiments I-1 to I-25, I-27 and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1a and R ^1b independently represent H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl , C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

[340] Embodiment I-38. The compound of any one of embodiments I-1 to I-25 and I-29 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1c and R ^1d independently represent H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O) R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl , 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

[341] Embodiment I-39. The compound of any one of embodiments I-1 to I-23, I-25, I-28, and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1e and R ^1f are independently represent H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

[342] Embodiment I-40. The compound of any one of embodiments I-1 to I-22, I-25 and I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1g and R ^1h independently represent H, halogen, -OR ^11a , -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ aryl , 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

[343] Embodiment I-41. The compound of any one of embodiments I-1 to I-25, I-27 and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1a and R ^1b independently represent H, -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[344] Embodiment I-42. The compound of any one of embodiments I-1 to I-25, I-27 and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1a and R ^1b independently represent H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ - C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[345] Embodiment I-43. The compound of any one of embodiments I-1 to I-25 and I-29 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1c and R ^1d are independently H, -C(O )R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[346] Embodiment I-44. The compound of any one of embodiments I-1 to I-25 and I-29 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1c and R ^1d are independently H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[347] Embodiment I-45. The compound of any one of embodiments I-1 to I-23, I-25, I-28, and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1e and R ^1f are independently represent H, -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C( O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[348] Embodiment I-46. The compound of any one of embodiments I-1 to I-23, I-25, I-28, and I-30 to I-33, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R ^1e and R ^1f are independently represent H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[349] Embodiment I-47. The compound of any one of embodiments I-1 to I-22, I-25 and I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1g and R ^1h independently represent H, -C(O) R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C (O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3-7 membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , -S(O )R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , NR ^11a C(O)NR ^12a and NR ^11a S(O) ₂ R ^12a ; and where the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(O)R ^11b , -P(O)R ^11b R ^12b , -S(O) ₂ R ^11b , - S(O)R ^11b , -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[350] Embodiment I-48. The compound of any one of embodiments I-1 to I-22, I-25 and I-33, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein R ^1g and R ^1h independently represent H, -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a , -NR ^11a S(O) ₂ R ^12a , C ₁ -C ₆ alkyl or 3 -7-membered heterocyclyl; wherein the C ₁ -C ₆ alkyl is substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C( O)NR ^12a and -NR ^11a S(O) ₂ R ^12a ; and wherein the 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR ^11a R ^12a , -NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a and -NR ^11a S(O) ₂ R ^12a .

[351] Embodiment I-49. The compound of any one of embodiments I-41 to I-48, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, wherein the 3-7 membered heterocyclyl contains nitrogen.

[352] Embodiment I-50. The compound of any one of embodiments I-1 to I-49, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the compound has the formula:

[353] Embodiment I-51. The compound of any one of embodiments I-1 to I-49, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the compound has the formula:

[354] Embodiment I-52. The compound of Embodiment I-1, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the compound is selected from the group consisting of

[355] Embodiment I-53. The compound of Embodiment I-1, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the compound is selected from the group consisting of

[356] Embodiment I-54. A pharmaceutical composition comprising a compound of any one of embodiments I-1 to I-53 or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof and a pharmaceutically acceptable carrier.

[357] Embodiment I-55. A method of treating a disorder susceptible to inflammasome inhibition, comprising administering an effective amount of a compound of any one of embodiments I-1 to I-53 to thereby treat the disorder in a subject in need thereof.

[358] Embodiment I-56. The method of embodiment I-55, wherein the disorder is a disorder that is susceptible to inhibition of NLRP3 inflammasome activation.

[359] Embodiment I-57. The method of embodiment I-54 or I-55, wherein the disorder is susceptible to modulation by one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL- 22, IL-33 and Th17 cells.

[360] Embodiment I-58. The method of embodiment I-54 or I-55, wherein the disorder is susceptible to modulation by one or more of IL-1β and IL-18.

[361] Embodiment I-59. The method of any one of embodiments I-55 to I-58, wherein the disorder is a disorder of the immune system.

[362] Embodiment I-60. The method of any one of embodiments I-55 to I-58, wherein the disorder is an inflammatory disorder or an autoimmune disorder.

[363] Embodiment I-61. The method of any one of embodiments I-55 to I-58, wherein the disorder is a liver disorder.

[364] Embodiment 1-62. The method of any one of embodiments I-55 to I-58, wherein the disorder is a pulmonary disorder.

[365] Embodiment I-63. The method of any one of embodiments I-55 to I-58, wherein the disorder is a skin disorder.

[366] Embodiment I-64. The method of any one of embodiments I-55 to I-58, wherein the disorder is a cardiovascular disorder.

[367] Embodiment I-65. The method according to any one of embodiments I-55 to I-58, characterized in that the disorder is an oncological disease, tumor or other malignant formation.

[368] Embodiment I-66. The method according to any one of embodiments I-55 to I-58, characterized in that the disorder is a disorder of the urinary system.

[369] Embodiment I-67. The method of any one of embodiments I-55 to I-58, wherein the disorder is a gastrointestinal disorder.

[370] Embodiment I-68. The method according to any one of embodiments I-55 to I-58, characterized in that the disorder is a disorder of the respiratory system.

[371] Embodiment I-69. The method of any one of embodiments I-55 to I-58, wherein the disorder is an endocrine system disorder.

[372] Embodiment I-70. The method of any one of embodiments I-55 to I-58, wherein the disorder is a central nervous system (CNS) disorder.

[373] Embodiment I-71. The method of any one of embodiments I-55 to I-58, wherein the disorder is selected from the group consisting of constitutive inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wels syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS) ), interleukin 1 receptor antagonist deficiency (DIRA), Majeed syndrome, suppurative arthritis, pyoderma and acne gangrenosum (PAPA), haploinsufficiency A20 (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO), and synovitis syndrome, acne, pustulosis, osteitis hyperostosis (SAPHO), autoimmune diseases including multiple sclerosis (MS), type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, central nervous system diseases, Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, metabolic diseases, type 2 diabetes, atherosclerosis, obesity, gout, pseudogout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye syndrome, kidney disease, chronic kidney disease, oxalate nephropathy , diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, inflammatory reactions of the skin, contact hypersensitivity, sunburn, inflammatory reactions in the joints, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, viral infections, alphavirus infection, chikungunya virus infection, Ross River virus infection, flavivirus infection, Dengue virus infection, Zika virus infection, influenza, HIV infection, hidradenitis suppurativa (HS), cystic skin diseases, oncological diseases, lung cancer metastases, pancreatic malignancies, gastric malignancies, myelodysplastic syndrome, leukemia, polymyositis, stroke, myocardial infarction, graft-versus-host disease, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, healing wounds, depression, psychological stress, pericarditis, Dressler's syndrome, ischemia-reperfusion injury, and any disease in which the individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[374] Embodiment I-72. The method of any one of embodiments I-55 to I-58, wherein the disorder is selected from the group consisting of a bacterial infection, a viral infection, a fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[375] Embodiment I-73. The method of embodiment I-68, wherein the disorder is non-alcoholic steatohepatitis (NASH).

[376] Embodiment I-74. The method of any one of embodiments I-55 to I-58, wherein the disorder is selected from the group consisting of lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease and inflammatory bowel disease (IBD).

[377] Embodiment I-75. The compound of any one of embodiments I-1 to I-53, or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof, for use as a drug.

[378] Embodiment I-76. The compound of any one of embodiments I-1 to I-53, or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, for use in treating a disorder that is susceptible to inflammasome inhibition.

[379] Embodiment I-77. Use of a compound of any one of embodiments I-1 to I-53 or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof in the manufacture of a medicament for the treatment of a disorder that is susceptible to inflammasome inhibition.

[380] Embodiment I-78. Pharmaceutical composition according to embodiment I-54 for use as a medicine.

[381] Embodiment I-79. The pharmaceutical composition of embodiment I-54 for use in the treatment of a disorder that is susceptible to inflammasome inhibition.

[382] Embodiment I-80. Use of the pharmaceutical composition of embodiment I-54 in the manufacture of a medicament for the treatment of a disorder that is susceptible to inflammasome inhibition.

Examples

[383] The following examples are provided to illustrate the present invention and should not be construed as limiting it. In these examples, all parts and percentages are by weight unless otherwise noted. The abbreviations used in the examples are given below.

Abbreviations

aq. - water

EtOAc - ethyl acetate

h - hour

HMDS - hexamethyldisilazide

HPLC - high performance liquid chromatography

HMDSL - lithium hexamethyldisilazide

min - minutes

ml - milliliter

mmol - millimole

MeOH - methanol

MeSO ₃ H - methanesulfonic acid

NMR - nuclear magnetic resonance

sat. - rich

sat. - saturated aqueous solution

NaHCO ₃ - NaHCO ₃

TEA - triethylamine

THF - tetrahydrofuran

TLC - thin layer chromatography

Analytical methods of chiral HPLC:

[384] Method A -

Column: Chiralcel OD-3 50×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: methanol (0.05% DEA)

Gradient: 5% to 40% B in 2 min and hold 40% for 1.2 min, then 5% B for 0.8 min

Flow rate: 4ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[385] Method B -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5ml/min

Column temperature: 40°С

AROD: 100 bar

[386] Method C -

Column: Chiralpak AS-3 100×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Gradient: 5% to 40% B in 4 min and hold 40% for 2.5 min, then 5% B for 1.5 min

Flow rate: 2.8ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[387] Method D -

Column: Chiralpak IC-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Gradient: 5% to 40% B in 5 min and hold 40% for 2.5 min, then 5% B for 2.5 min

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[388] Method E -

Column: Chiralpak AD-3 50×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Gradient: 5% to 40% B in 2 min and hold 40% for 1.2 min, then 5% B for 0.8 min

Flow rate: 4ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[389] Method F -

Column: Chiralpak IC-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5ml/min

Pace. columns: 40°C

AROD: 100 bar

[390] Method G -

Column: Cellulose 2 150×4.6 mm i.d. d., 5 µm

Mobile phase: A: CO ₂ B: Methanol (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[391] Method H -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: 40% methanol (0.05% DEA) in CO ₂

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[392] Method I -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: 40% ethanol (0.05% DEA) in _CO2

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[393] Method J-

Column: Chiralcel OJ-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Gradient: from 5% to 40% B in 5 min and from 40% to 5% B in 0.5 min, holding 5% B for 1.5 min

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[394] Method K -

Column: Chiralcel OD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: methanol (0.05% DEA)

Gradient: 5% to 40% B in 5 min and hold 40% for 2.5 min, then 5% B for 2.5 min

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[395] Method L -

Column: Chiralpak IC-3 150×4.6 mm h. d., 3 µm

Mobile phase: 40% ethanol (0.05% DEA) in _CO2

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[396] Method M -

Column: ChiralCel OD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: Methanol (0.05% DEA)

Gradient: 5% to 40% B in 5.5 min and hold 40% for 3 min, then 5% B for 1.5 min

Flow rate: 2.5ml/min

Pace. columns: 40°C

AROD: 100 bar

[397] Method N -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Gradient: 5% to 40% B in 5 min and hold 40% for 2.5 min, then 5% B for 2.5 min

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[398] Method O -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: Methanol (0.05% DEA)

Gradient: 5% to 40% B in 5.5 min and hold 40% for 3 min, then 5% B for 1.5 min

Flow rate: 2.5ml/min

Pace. columns: 40°C

Back pressure: 100 bar

[399] Method P -

Column: Cellulose 2 150×4.6 mm i.d. d., 5 µm

Mobile phase: A: CO ₂ B: ethanol (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[400] Method Q -

Column: Chiralcel OD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: methanol (0.05% DEA)

Gradient: from 5% to 40% B in 5 min and from 40% to 5% B in 0.5 min, holding 5% B for 1.5 min

Flow rate: 2.5ml/min

Pace. columns: 35°C

AROD: 1500 psi. inch

[401] Method R -

Column: Chiralcel OJ-H 150×4.6 mm h. d., 5 µm

Mobile phase: A: CO ₂ B: IPA (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5ml/min

Pace. columns: 40°C

AROD: 100 bar

[402] Method S -

Column: Chiralpak AD-3 150×4.6 mm h. d., 3 µm

Mobile phase: A: CO ₂ B: Ethanol (0.05% DEA)

Gradient: 5% to 40% B in 5.5 min and hold 40% for 3 min, then 5% B for 1.5 min

Flow rate: 2.5ml/min

Pace. columns: 40°C

AROD: 100 bar

[403] Method T -

Column: Chiracel OX, 50×4.6 mm, h. d. 3 µm

Mobile phase: A: CO ₂ B: methanol (0.1% NH ₄ OH)

Gradient: Isocratic at 30% B

Flow rate: 4ml/min

Temp, columns: 40°C

AROD: 120 bar

[404] Method U -

Column: Chiralpak IA, 50×4.6 mm, h. d. 3 µm

Mobile phase: A: CO ₂ B: methanol (0.1% NH ₄ OH)

Gradient: Isocratic at 35% B

Flow rate: 4ml/min

Pace. columns: 40°C

AROD: 120 bar

[405] Method V -

Column: Chiracel OX, 50×4.6 mm, h. d. 3 µm

Mobile phase: A: CO ₂ B: methanol (0.1% NH ₄ OH)

Gradient: Isocratic at 40% B

Flow rate: 4ml/min

Pace. columns: 40°C

AROD: 120 bar

[406] Method W -

Column: WhelkO-1(s,s), 100×4.6 mm, h. d. 3 µm

Mobile phase: A: CO ₂ B: ethanol (0.1% NH ₄ OH)

Gradient: Isocratic at 30% B

Flow rate: 4ml/min

Pace. columns: 40°C

AROD: 125 bar

Synthesis examples

Example A

Synthesis of armored pyrazolo[5,1-b][1,3]oxazine: (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine

Step 1 - Synthesis of 1-acetyl-1,2-dihydro-pyrazol-3-one:

[407] A solution of 1,2-dihydropyrazol-3-one (50.0 g, 600 mmol) in pyridine (300 ml) was heated to 95°C. A solution of acetic anhydride (61.2 g, 600 mmol) in pyridine (100 ml) was slowly added to the solution over 0.5 hour. The reaction mixture was heated for an additional 1 hour at 95°C. The reaction mixture was concentrated in vacuo to give a dark red oil, which was triturated with MeOH (150 ml) and filtered to give 1-acetyl-1,2-dihydropyrazol-3-one (54.0 g, yield: 71%) as a white solid. ^1H NMR (300 MHz, DMSO- _d6 ): δ=10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H), 2.45 (overlap, 3H) .

Step 2 - Synthesis of (S)-1-(3-(oxiran-2-ylmethoxy)-1H-pyrazol-1-yl)ethan-1-one:

[408] A mixture of 1-acetyl-1,2-dihydropyrazol-3-one (34.7 g, 280 mmol) and PPh ₃ (24.9 g, 420 mmol) in THF (400 ml) was cooled to 0° C in an atmosphere of N ₂ . DIAD (84.8 g, 420 mmol) was slowly added to the mixture. The reaction mixture was stirred for 1 hour at 0°C, then (I)-oxiran-2-ylmethanol (25.2 g, 340 mmol) was added slowly. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified using a silica gel column (PE/EtOAc=10/1) to give (S)-1-(3-(oxiran-2-ylmethoxy)-1H-pyrazol-1-yl)ethane -1-one (34.8 g, yield: 68%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ=8.06 (d, J=2.8 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H), 4.55 (dd , J=12.0, 3.2 Hz, 1H), 4.20 (dd, J=12.0, 3.2 Hz, 1H), 3.39 (k, J=3.2 Hz, 1H) , 2.92 (t, J=4.4 Hz, 1H), 2.76 (dd, J=4.4, 2.4 Hz, 1H), 2.57 (s, 3H).

Step 3 - Synthesis of (R)-1-(3-(3-chloro-2-hydroxypropoxy)-1H-pyrazol-1-yl)ethan-1-one:

[409] In a solution of (S)-1-(3-(oxiran-2-ylmethoxy)-1H-pyrazol-1-yl)ethan-1-one (34.8 g, 190 mmol) in AcOH (34.2 g, 570 mmol) and THF (200 ml), LiCl (13.1 g, 310 mmol) was added at room temperature. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was washed with saturated aqueous NaHCO ₃ (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude (R)-1-(3-(3-chloro-2-hydroxypropoxy )-1H-pyrazol-1-yl)ethan-1-one as a colorless oil, which was directly used in the next step without any purification. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=8.25 (d, J=2.7 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 5.59 (broad s, 1H), 4.24-4.19 (m, 2H), 4.07-4.04 (m, 1H), 3.75-3.62 (m, 2H), 2.50 (overlap, 3H). MS: m/z 219.4 (M+H ⁺ ).

Step 4 Synthesis of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol:

[410] Mixture of (R)-1-(3-(3-chloro-2-hydroxypropoxy)-1H-pyrazol-1-yl)ethan-1-one (crude, 190 mmol) and K ₂ CO ₃ (78.7 g , 570 mmol) in DMF (400 ml) was stirred at 135°C overnight. The solvent was removed under reduced pressure. The residue was purified using a silica gel column (EtOAc) to give (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.8 g, yield: 48 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.21 (d, J=1.6 Hz, 1H), 5.51 (d, J=3.2 Hz, 1H), 5.44 (d, J=1.6 Hz, 1H), 4.24-4.13 (m, 4H), 3.92 (d, J=12.4 Hz, 1H).

Step 5 - Synthesis of (S)-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol:

[411] In a solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.8 g, 91.4 mmol) in MeCN (200 ml) NBS (17.9 g, 100.6 mmol) was added in two parts at 0° C. under N ₂ atmosphere. The reaction mixture was warmed to room temperature and left stirring for 1 hour. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was washed with saturated aqueous NaHCO ₃ (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was triturated with EtOAc (50 ml) and filtered to give (S)-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (11, 3 g, yield: 57%) as a white solid. MS: m/z 219.3 (M+H).

Step 6 - Synthesis of (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine:

[412] In solution of (S)-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.2 g, 55.7 mmol) in DMF (60 ml) was added NaH (60% in mineral oil, 2.7 g, 66.8 mmol) under N ₂ at room temperature. After 1 hour, MeI (9.5 g, 66.8 mmol) was added. The reaction mixture was left stirring for an additional 2 hours at room temperature. The reaction mixture was then poured into water (200 ml) and extracted with EtOAc (100 ml x 2). The organic layer was washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The crude residue was triturated with MeOH/H ₂ O (2/1, 100 ml) and filtered to give (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine (9.5 g, yield: 73%) as a white solid. MS: m/z 233.3 (M+H ⁺ ).

Example 1

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonimidamide

Step 1 - Synthesis of N-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide:

[413] Into a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (1.0 g, 4.9 mmol) in dry THF (20 ml) slowly n-BuLi (2.5 M in hexane, 2.4 ml, 5.9 mmol) was added at -78°C under N ₂ atmosphere. After stirring with cooling for 2 hours, TBSOTf (1.6 g, 5.9 mmol) was added slowly. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with sat. aqueous NH ₄ Cl solution (10 ml), and the resulting solution was directly purified using a reverse phase column (MeCN/H ₂ O) to obtain N-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide (610 mg, yield: 38%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 7.36 (s, 1H), 4.40 (t, J=5.2 Hz, 2H), 4 .11 (t, J=6.0 Hz, 2H), 2.20-2.15 (m, 2H), 0.87 (s, 9H), 0.11 (s, 6H). MS: m/z 318.3 (M+H ⁺ ).

Step 2 - Synthesis of N'-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimide amide:

[414] Triethylamine (125 mg, 1.5 mmol) was added to a stirred suspension of Ph ₃ PCl ₂ (363 mg, 1.1 mmol) in dry CHCl ₃ (3.0 ml) under N ₂ atmosphere. The mixture was stirred for 10 minutes at room temperature, after which a yellow suspension immediately formed. The reaction mixture was cooled to 0°C and a solution of N-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (316 mg, 1. 0 mmol) in dry CHCl ₃ (3 ml). After stirring for 20 minutes at 0°C, NH ₃ gas was bubbled through the mixture for 10 minutes at 0°C. The resulting solution was then stirred for 30 minutes at room temperature and then concentrated to dryness. The residue was purified using a reverse phase column (MeCN/H ₂ O) to give N'-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide (mixture with Ph ₃ P=O), which was directly used in the next step without additional purification. MS: m/z 317.3 (M+H ⁺ ).

Step 3 - Synthesis of N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[415] A suspension of N'-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (~1.0 mmol) in MeOH (10 ml) was stirred at 80°C to obtain a clear solution. MeONa (54 mg, 1.0 mmol) was added and the mixture was stirred for 5 minutes. The solution was concentrated to dryness and the residue was evaporated with MeCN (5 ml). The residual solid was suspended in MeCN (5 mL) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (199 mg, 1.0 mmol) was added at room temperature. After 16 hours, the reaction mixture was filtered. The solid was dried to give N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide as a white solid, which was used in the next step without further purification.

Step 4 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (example 1)

[416] In a solution of N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (40 mg, 0.08 mmol) in DCM (5 ml) was added with HCl/dioxane (2 M, 2 ml) at room temperature. After 2 hours, the reaction mixture was first purified using a reverse phase column (MeCN/H ₂ O) to obtain the crude product. The crude product was then purified by preparative HPLC (NH ₃ ⋅H ₂ O) to give N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (4.6 mg, yield: 15%, mixture of enantiomers) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.18 (br s, 1H), 7.50 (s, 1H), 7.23 (br s, 2H), 6.85 ( s, 1H), 4.39 (t, J=6.4 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.20-2.15 (m, 2H), 1.96-1.89 (m, 4H). MS: m/z 402.1 (M+H ⁺ ).

Example 2

(6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide

Step 1 - Synthesis of (S)-N-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide:

[417] Into a suspension of (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (2.0 g, 8.6 mmol) Et ₃ N (2.1 g, 21.5 mmol) and TBSOTf (3.0 g, 11.2 mmol) were added to THF (20 ml) at room temperature. After stirring at 50°C for 16 hours, the reaction mixture was cooled to room temperature, concentrated and purified using a reverse phase column (5% ~ 95% MeCN in H ₂ O) to give (S)-N-(tert- butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (2.6 g, yield: 87%) as a yellow solid. MS: m/z 348.3 (M+H ⁺ ).

Step 2 - Synthesis of (6S)-N-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[418] To a suspension of Ph ₃ PCl ₂ (1.8 g, 5.5 mmol) in CHCl ₃ (15 ml) was added Et ₃ N (860 mg, 8.6 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hour, then (S)-N-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] was added ]oxazine-3-sulfonamide (1.6 g, 4.6 mmol) in CHCl ₃ (5 ml) at 0°C. The reaction mixture was stirred at room temperature for an additional 2 hours, then NH ₃ (gas) was bubbled through the mixture for 5 minutes. The resulting solution was stirred for 30 minutes at room temperature and concentrated to dryness. The residue was purified by a silica gel column (DCM/MeOH=20/1) to give (6S)-N'-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (920 mg, mixed with Ph ₃ PO) as a yellow solid. MS: m/z 347.3 (M+H ⁺ ).

Step 3 - Synthesis of (6S)-N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[419] Into a suspension of (6S)-N'-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (110 mg, mixture with Ph ₃ PO) in THF (2 ml) was added MeONa (19 mg, 0.35 mmol) and the mixture was stirred at room temperature for 20 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (75 mg, 0.4 mmol) was then added and the resulting mixture was stirred at room temperature for 16 hours. Then into the above suspension water (0.5 ml) was added. The precipitate was collected by filtration and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (45 mg, purity: 62 %) as a white solid. MS: m/z 546.4 (M+H ⁺ ).

Step 4 - Synthesis of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 2):

[420] Into a suspension of (6S)-N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (45 mg, purity: 62%) in MeOH (0.5 ml) was added HCl/dioxane (2 M, 2 ml) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was concentrated and purified using a reverse phase column (5-95% MeCN in H ₂ O) to give (6S)-N-((1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (7 mg , yield: 21%, mixture of stereoisomers) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.22 (br s, 1H), 7.56 (d, J=5.2 Hz, 1H), 7.31 (br s, 2H), 6.89 (s, 1H), 4.63 (d, J=7.2 Hz, 1H), 4.37-4.19 (m, 3H), 4.07 (s, 1H), 3.38 (overlap, 3H), 2.86-2.67 (m, 8H), 2.02-1.91 (m, 4H). MS: m/z 432.2 (M+H ⁺ ).

Example 3

N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[421] The title compound was prepared according to the general procedure for the preparation of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide to obtain a mixture of stereoisomers. In particular, N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was obtained in the form mixtures of enantiomers using the general procedure described for the preparation of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide (example 1), replacing 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene with 5-fluoro-2- isocyanato-1,3-diisopropylbenzene in step 3. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.01 (s, 1H), 7.49 (s, 1H), 7.23 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 4.40-4.35 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.14-3.08 (m, 2H), 2.18-2.15 (m, 2H), 1.16-1.07 (m, 12H). MS: m/z 424.2 (M+H ⁺ ).

Example 4

N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonimidamide

[422] The title compound was prepared using the general procedure for the preparation of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide. N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonimidamide was prepared as a mixture of enantiomers using the general procedure described for the preparation of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 1), replacing 4-isocyanato-1,2,3,5,6,7 -hexahydro-s-indacene to 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene in step 3. ^1H NMR (400 MHz, DMSO- _d6 ): δ =8.22 (br. s, 1H), 7.50 (s, 1H), 7.23 (s, 2H), 4.40-4.35 (m, 2H), 4.10 (t, J =6.0 Hz, 2H), 2.82 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.20-2.17 (m , 2H), 2.01-1.96 (m, 4H). MS: m/z 420.1 (M+H ⁺ ).

Example 5

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-4-sulfonimidamide

[423] N'-((1,2,3,5,6,7-hexahydro-3-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-4-sulfonimidamide was prepared as a mixture of enantiomers, using the general procedure described for the preparation of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 6), replacing 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonamide to 1-methyl-1H-pyrazole-4-sulfonamide in Step 1 to obtain the title compound as a mixture of stereoisomers. MS: m/z 360 (M+H ⁺ ).

Example 6

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of N-[-(tert-butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide:

[424] A solution of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (1.5 g, 6.5 mmol) in THF ( 28 ml), stirred under nitrogen at 0°C, was treated with sodium hydride (60%, 0.31 g, 7.8 mmol). After 20 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (2.3 g, 8.4 mmol) was added dropwise over 5 minutes. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 13 hours. The reaction mixture was then quenched by adding saturated NH ₄ Cl solution (10 ml). The aqueous mixture was extracted with EtOAc (3 X 20 ml). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated to leave a colorless semi-solid residue. The resulting residue was purified using a silica gel column (0 to 30% EtOAc in DCM). The clear fractions were combined to give N-(tert-butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (1.15 g , 51%) as a white solid. MS: m/z 346 (M+H ⁺ ).

Step 2 - Synthesis of N'-(tert-butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[425] A suspension of triphenylphosphine dichloride (1.16 g, 3.5 mmol) stirred in CHCl ₃ (12 ml) at 0° C. under nitrogen was treated with Et ₃ N (0.52 ml, 3.8 mmol) for 5 minutes. The ice bath was removed and the mixture was stirred for 15 minutes (forming a white slurry). After cooling the mixture to 0°C, a solution of N-(tert-butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide ( 1 g, 2.9 mmol) in CHCl ₃ (12 ml). After stirring the mixture for 20 minutes, the ice bath was removed and the mixture was stirred for 20 minutes. The mixture was cooled to 0°C and treated with 0.5 M ammonia (20 ml, 11.6 mmol) in 1,4 dioxane. After stirring the mixture for 30 minutes, the ice bath was removed and the mixture was stirred for an additional 1 hour. After treating the mixture with water (50 ml), the mixture was concentrated until only water remained; the resulting aqueous mixture was extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated. The resulting solid was purified using a silica gel column (0 to 100% EtOAc in DCM). Triphenylphosphine oxide was added to the fractions containing the desired product. The fractions were combined and concentrated to give a white solid. The solid was treated with a solution of 20% EtOAc in hexanes (20 ml), sonicated and left to settle for 20 minutes until a precipitate formed. The suspension was filtered (the solid was determined to be triphenylphosphine oxide) and the filtrate was concentrated to dryness to give N'-(tert-butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonidamide (850 mg) with an admixture of triphenylphosphine oxide. The material was transferred further without any additional purification. MS: m/z 345 (M+H ⁺ ).

Step 3 - Synthesis of N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[426] N'-(tert-Butyldimethylsilyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide solution (400.0 mg , 0.35 mmol, 30% w/w), stirred in DMF (4 ml) at 0°C under nitrogen, treated with NaH (60%, 18 mg, 0.45 mmol). After 15 minutes, the mixture was treated with 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (76 mg, 0.38 mmol). The ice bath was removed and the mixture was stirred for an additional 2 hours. The mixture was treated with saturated NH ₄ Cl solution and extracted with EtOAc (3 X 20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting precipitate was diluted with MeOH, treated with ultrasound, and left to settle for 2 hours. After filtering the suspension, the filter cake was washed with additional MeOH. The filtrate was evaporated to dryness to give N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (180 mg) with an admixture of triphenylphosphine oxide. The material was transferred further without any additional purification. MS: m/z 544 (M+H ⁺ ).

Step 4 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide (example 6):

[427] A solution of N'-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (180 mg, 0.07 mmol), stirred in 1,4 dioxane (2 ml), treated with 4 N HC1 solution (2 ml, 6.6 mmol) in 1,4 dioxane. The ice bath was removed and the mixture was stirred for 15 minutes before concentration. The resulting solid was diluted with MeOH (30 ml), sonicated and allowed to settle for 30 minutes before filtration. After concentrating the filtrate to dryness, the resulting solid was suspended in ethyl ether (20 ml), sonicated and filtered (the white filter cake was triphenylphosphine oxide; the filtrate contained the desired product along with the remaining triphenylphosphine oxide and other by-products). After concentrating the filtrate, trituration with ethyl ether was repeated two more times. The filtrate after the last trituration was concentrated. The resulting solid was diluted in MeOH (5 ml) to obtain a light suspension. The suspension was filtered through a 0.45 A syringe filter; the filtrate was purified using preparative LCMS (05-95% ACN, 0.1% NH ₄ Cl). Fractions were collected and concentrated to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide as a white solid (6 mg, mixture of stereoisomers). MS: m/z 430 (M+H ⁺ ).

Example 7 and Example 8

(S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and ( R)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide

[428] Steps 1 and 2. These two steps were carried out similarly to the general procedure for the preparation of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide.

[429] (S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonimidamide and (R)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonidamide: N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (80 mg, 0.2 mmol) was separated by chiral preparative HPLC to give two isomers of unknown absolute stereochemistry as white solids.

[430] Peak 1, 21.4 mg, yield: 27% ^1H NMR (400 MHz, DMSO- _d6 ): δ=7.99 (s, 1H), 7.49 (s, 1H), 7. 23 (br. s, 2H), 6.86 (s, 1H), 6.84 (s, 1H), 4.40-4.35 (m, 2H), 4.10 (t, J=6, 0 Hz, 2H), 3.14-3.08 (m, 2H), 2.18-2.15 (m, 2H), 1.16-1.07 (m, 12H). MS: m/z 424.2 (M+H ⁺ ).

[431] Peak 2, 18.1 mg, yield: 23% ^1H NMR (400 MHz, DMSO- _d6 ): δ=7.99 (s, 1H), 7.49 (s, 1H), 7. 24 (br. s, 2H), 6.87 (s, 1H), 6.84 (s, 1H), 4.40-4.35 (m, 2H), 4.10 (t, J=6, 0 Hz, 2H), 3.14-3.08 (m, 2H), 2.18-2.15 (m, 2H), 1.16-1.07 (m, 12H). MS: m/z 424.2 (M+H ⁺ ).

Example 9

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-methyl-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of N'-(tert-butyldimethylsilyl)-N-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[432] Triethylamine (0.42 g, 4.2 mmol) was added to a stirred suspension of triphenylphosphine dichloride (1.2 g, 3.5 mmol) in dry CHCl ₃ (4.5 ml) under N ₂ atmosphere. The reaction mixture was stirred for 10 min at room temperature (to form a white suspension). Then the reaction mixture was cooled to 0°C and a solution of N-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0. 44 g, 1.4 mmol) in dry CHCl ₃ (3.5 ml). The reaction mixture was heated to 10°C for 1 hour, then cooled again to 0°C, and a 2 M solution of methamine (3 ml, 6.9 mmol) in THF was added dropwise. The reaction mixture was stirred at 0°C for 20 minutes, then warmed to room temperature over 2 hours. The reaction mixture was then concentrated to dryness and the residue was purified by silica gel chromatography (30 to 100% EtOAc in hexanes, then 0 to 10% MeOH in DCM) to give N'-(tert-butyldimethylsilyl)-N-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (0 .25 g, ~ 85% w/w) with an admixture of triphenylphosphine oxide. The material was used in the next step without additional purification. MS: m/z 331 (M+H ⁺ ).

Step 2 - Synthesis of N'-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[433] In a solution of N'-(tert-butyldimethylsilyl)-N-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (0.25 g, ~0.64 mmol, !85% w/w) in CH ₃ CN (3 ml), cooled to 10°C, add a solution of 4 N HCl (0.9 ml, 3.8 mmol) in 1.4 -dioxane. The reaction mixture was warmed to room temperature for 2 hours. The reaction mixture was then concentrated to dryness and the residue was purified by preparative HPLC (CH ₃ CN/H ₂ O/10 mM aq. NH ₃ ) to give N'-methyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (78 mg, yield: 48%) as a colorless oil. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ=7.44 (s, 1H), 6.32 (br s, 1H), 4.41-4.35 (m, 2H), 4, 11 (t, J=6.1 Hz, 2H), 3.71 (br s, 1H), 2.41 (s, 3H), 2.22-2.17 (m, 2H). MS: m/z 217 (M+H ⁺ ).

Step 3 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-methyl-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide (example 9):

[434] In a solution of N'-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (44 mg, 0.20 mmol) in DMF (1 ml ), cooled to 0°C, sodium hydride (60%, 8.1 mg, 0.20 mmol) was added under N ₂ atmosphere, the reaction mixture was stirred for 10 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (41 mg, 0.20 mmol) was then added in one portion and the ice-water bath was removed. The reaction mixture was stirred at room temperature for 62 hours. The reaction mixture was quenched with MeOH, filtered and purified by preparative HPLC (CH ₃ CN/H ₂ O/10 mM aq. NH ₃ ) to give N-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonimidamide (9.2 mg, yield: 11%, mixture of stereoisomers) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ=8.26 (br s, 1H), 7.50 (s, 1H), 7.11 (br s, 1H), 6.87 ( s, 1H), 4.45-4.36 (m, 2H), 4.13 (t, J=6.1 Hz, 2H), 2.79 (t, J=7.3 Hz, 4H), 2.71 (t, J=7.3 Hz, 4H), 2.49 (s, 3H), 2.25-2.17 (m, 2H), 1.98-1.92 (m, 4H) . MS: m/z 416 (M+H ⁺ ).

Example 10

1-(cyclopropylmethyl)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-4-sulfonimidamide

[435] 1-(cyclopropylmethyl)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-4-sulfonimidamide was prepared as a mixture enantiomers using the general procedure described for the preparation of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 6), replacing 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonamide to 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide in Step 1 to give the title compound as a mixture of stereoisomers. MS: m/z 400 (M+H ⁺ ).

Example 11 and Example 12

N'-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonidamide and N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonidamide

Step 1 Synthesis of methyl 1-methyl-1H-pyrazole-3-sulfinate:

[436] A solution of sodium sulfite (1.4 g, 2 eq. 11 mmol) and sodium bicarbonate (0.93 g, 2 eq. 11 mmol) in water (6 ml) was heated to 80°C and a solution of 1- Methyl 1H-pyrazole-3-sulfonyl chloride (1.0 g, 1 eq. 5.5 mmol) in 1,4-dioxane (6 ml). The reaction mixture was stirred at the same temperature for 1 hour before concentration under reduced pressure. Ethanol (100 ml) was added and the mixture was refluxed for 1 hour before the supernatant was separated while the reaction mixture was hot. Additional ethanol (100 ml) was added to the residue and the mixture was stirred at room temperature for 30 min before filtration. The filtrates were combined and the ethanol was removed under reduced pressure to obtain a white solid.

[437] The resulting solid was suspended in chloroform (10 ml) and thionyl chloride (0.86 g, 0.53 ml, 1.3 eq. 7.2 mmol) was added dropwise at 0° C. under N ₂ atmosphere. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour (solution A). In a separate flask, TEA (1.7 g, 2.3 mL, 3 eq. 16 mmol), methanol (0.89 g, 1.1 mL, 5 eq. 28 mmol) in THF (10 mL) was cooled to -78 °C, solution A was slowly added under N ₂ atmosphere. The reaction mixture was heated to 0°C and stirred for 1 hour. TLC (10% MeOH/DCM) showed completion of the reaction. The mixture was diluted with EtOAc and washed with water, brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel chromatography (0 to 100% EtOAc/hexane) to give methyl 1-methyl-1H-pyrazole-3 -sulfinate (503 mg, 56%, mixture of stereoisomers) as white solids. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.93 (s, 1H), 6.68 (s, 1H), 3.93 (s, 3H), 3.52 (s, 3H). LCMS: m/z 161 [M+H] ⁺ .

Steps 2 and 3 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide:

[438] To a solution of methyl 1-methyl-1H-pyrazole-3-sulfinate (400 mg, 1 equiv. 2.5 mmol) in anhydrous THF (3 ml) was added HMDSL (627 mg, 3.7 mmol, 1.5 eq. 3.75 mmol, 1 M in THF) in an atmosphere of N ₂ . The reaction mixture was warmed to room temperature and stirred for 2 hours before adding 1 ml of saturated NH4C1 solution and stirring the mixture for an additional 1 hour. EtOAc (50 ml) was then added and the resulting solution was dried over Na ₂ SO ₄ . The mixture was filtered and the solvent was removed to give crude 1-methyl-1H-pyrazole-3-sulfinamide (363 mg, 100%) as white solids. The product was used in the next step without further purification.

[439] 1-Methyl-1H-pyrazole-3-sulfinamide (363 mg, 1 equiv. 2.5 mmol), prepared as described above, was dissolved in anhydrous DMF (3 ml). To this solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (495 mg, 1 eq. 2.5 mmol), followed by NaH (0.2 g, 2 eq. 5.00 mmol, 60% by weight) at room temperature. The mixture was stirred for 1 h before quenching with 1 ml MeOH. The mixture was purified by preparative HPLC to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide (190 mg, 22%) as white solids. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.76 (s, 1H), 6.85 (s, 1H), 6.62 (s, 1H), 3.88 (s, 3H), 2 .80 (t, 4H), 2.73 (t, 4H), 1.95 (t, 4H). LCMS: m/z=367 [M+Na] ⁺ .

Synthesis of N'-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimide amide

Step 4 Synthesis of N-benzyl-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonidamide

Into a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide (50.0 mg, 1 eq. . 145 µmol) in anhydrous acetonitrile (1 ml) was added NCS (29.1 mg, 1.5 eq. 218 µmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour before benzyamine (31.1 mg, 32 μl, 2 eq. 290 μmol) was added dropwise under N ₂ . The reaction mixture was stirred at room temperature for 1 hour before adding water (10 ml). The mixture was extracted with EtOAc (3 x 10 ml), the combined organic extracts were washed with water, brine and dried over Na ₂ SO ₄ and concentrated, purified by silica gel chromatography (EtOAc/hexane 0 to 100%, followed by MeOH/DCM from 0 to 10%) to obtain N'-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazol- 3-sulfonimidamide (35 mg, 54%, mixture of stereoisomers) as white solids. LCMS: m/z 450 [M+H] ⁺ .

Step 5 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonidamide

Into a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide (50.0 mg, 1 eq. . 145 µmol) in anhydrous acetonitrile (1 ml) was added NCS (29.1 mg, 1.5 eq. 218 µmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour before adding dropwise HMDS (46.9 mg 61 μl, 2 eq. 290 μmol) under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 1 hour and the crude mixture was purified by preparative HPLC to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 1-Methyl-1H-pyrazole-3-sulfonimidamide (4 mg, 8%, mixture of stereoisomers) as white solids. LCMS: m/z 360 [M+H] ⁺ .

Example 13 and Example 14

(R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-3-sulfonidamide and (S)-N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[440] Into a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.1 g, 5.4 mmol) in THF (20 ml) dropwise add n-BuLi (2.4 ml, 5.9 mmol, 2.5 M in hexane) at -78°C and stir the mixture at this temperature for 1 hour. A solution of TrtNSO (1.8 g, 5.9 mmol) in THF (10 ml) was added dropwise and the mixture was stirred at -78°C for 20 minutes before placing in an ice bath. After stirring for an additional 10 minutes, tert-butyl hypochlorite (650 mg, 5.9 mmol) was added and the mixture was stirred for 20 minutes. NH ₃ gas was then bubbled through the mixture for 5 minutes and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and the residue was purified using a reverse phase column (MeCN/H ₂ O) to give N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazine-3-sulfonidamide (716 mg, yield: 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.43-7.41 (m, 6H), 7.20-7.15 (m, 6H), 7.11-7.07 (m , 3H), 6.99 (s, 1H), 6.20 (br. s, 2H), 4.20-4.19 (m, 2H), 3.97-3.89 (m, 2H), 2.10-2.07 (m, 2H).

Step 2 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide:

[441] In a solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (716 mg, 1.6 mmol) in THF (10 ml ) MeONa (96 mg, 1.8 mmol) was added and the mixture was stirred for 30 minutes at room temperature. 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (375 mg, 1.7 mmol) was then added and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -N'-Trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (370 mg, yield: 36%) as a white solid. MS: m/z 644.3 (M+H ⁺ ).

Step 3 - (R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazin-3-sulfonidamide and (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[442] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (350 mg, 0.5 mmol) was separated by chiral preparative HPLC to give two isomers, (R)-N-((1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide and (S )-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonimidamide, with unknown stereochemistry as white solids (peak 1, 80 mg, yield: 23%; peak 2, 150 mg, yield: 43%).

Step 4 - Synthesis of (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazin-3-sulfonidamide and (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 13 and example 14):

To a solution of the material collected from peak 1 (80 mg, 0.1 mmol) in DCM (5 ml) two drops of methanesulfonic acid were added. After stirring at room temperature for 5 hours, the reaction solution was adjusted to pH=8 using sat. NaHCO ₃ , concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to obtain the crude product. The crude product was further purified by preparative HPLC (NH ₃ ⋅H ₂ O) to give (R)-N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (2.2 mg, yield: 5%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.01 (s, 1H), 7.43 (s, 1H), 6.82 (s, 1H), 6.71 (br s, 1H), 4.35 (t, J=4.4 Hz, 2H), 4.08 (t, J=6.0 Hz, 2H), 2.77 (t, J=7.2 Hz, 4H) , 2.67 (t, J=7.2 Hz, 4H), 2.17-2.15 (m, 2H), 1.96-1.89 (m, 4H). MS: m/z 402.1 (M+H ⁺ ).

[443] To a solution of the material collected from peak 2 (80 mg, 0.1 mmol) in DCM (4 ml) was added two drops of methanesulfonic acid. After stirring at room temperature for 0.5 hours, the reaction mixture was adjusted to pH=8 by adding sat. NaHCO ₃ The precipitate was collected by filtration and dried to give (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (10 mg, yield: 23%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.17 (s, 1H), 7.50 (s, 1H), 7.21 (s, 2H), 6.85 (s, 1H) , 4.41 (t, J=3.2 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 2.77 (t, J=7.2 Hz, 4H), 2 .67 (t, J=7.2 Hz, 4H), 2.19-2.15 (m, 2H), 1.96-1.89 (m, 4H). MS: m/z 402.1 (M+H ⁺ ).

Example 15

(6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide

Step 1 - Synthesis of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[444] In a solution of (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.0 g, 4.3 mmol) n-BuLi (1.8 mL, 4.3 mmol, 2.5 M in hexane) was added dropwise to THF (10 mL) at -78° C. and the mixture was stirred at this temperature for 0.5 hour. A solution of TrtNSO (1.3 g, 4.3 mmol) in THF (5 ml) was added dropwise and the mixture was stirred at -78°C for 30 minutes before placing in an ice bath. After stirring for a further 10 minutes, tert-butyl hypochlorite (480 mg, 4.5 mmol) was added and the mixture was stirred for 20 minutes. NH ₃ gas was then bubbled through the mixture for 10 minutes and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonidamide (400 mg, yield: 20%) as a yellow solid.

Step 2 - Synthesis of (6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide:

[445] In a solution of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (100 mg, 0. 2 mmol) in THF (2 ml) was added MeONa (13 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 20 minutes to obtain a sodium salt suspension.

[446] In a separate flask, triethylamine (75 mg, 0.8 mmol) and triphosgene (29 mg) were added in one part to a solution of 4-fluoro-2,6-diisopropylaniline (49 mg, 0.3 mmol) in THF (3 ml). , 0.1 mmol) at 0°C. After stirring at room temperature for 10 minutes under N ₂ atmosphere, the reaction mixture was filtered. The filtrate was added to the above sodium salt suspension. The new reaction mixture was stirred at room temperature for 16 hours, then concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl )-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (49 mg, 33%) as a yellow solid. MS: m/z 696.4 (M+H ⁺ ).

Step 3 - Synthesis of (6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide (example 15):

[447] Into a solution of (6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonidamide (80 mg, 0.1 mmol) in THF (1.5 ml) was added MeSO ₃ H (6 drops) at 0°C. After stirring at this temperature for 0.5 hour, the reaction mixture was concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (32 mg, 59%, mixture of diastereomers) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.99 (s, 1H), 7.52-7.49 (m, 1H), 7.13 (br s, 2H), 6. 88 (s, 1H), 6.85 (s, 1H), 4.64-4.50 (m, 1H), 4.31-4.14 (m, 3H), 4.04 (s, 1H) , 3.37 (overlap, 3H), 3.20-3.06 (m, 2H), 1.15-1.02 (m, 12H). MS: m/z 454.1 (M+H ⁺ ).

Example 16

(6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonimidamide:

[448] The title compound was prepared using the general procedure for the preparation of (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, to obtain a mixture of stereoisomers. (6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonimidamide was prepared as a mixture of diastereomers using the general procedure described for the preparation of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 17), replacing 4-isocyanato-1,2,3,5 ,6,7-hexahydro-s-indacene to 5-fluoro-2-isocyanato-1,3-diisopropylbenzene in step 2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.03 (d, J =10.0 Hz, 1H), 7.50 (s, 1H), 7.23 (br. s, 2H), 6.86 (s, 1H), 6.84 (s, 1H), 4.40 -4.19 (m, 3H), 3.92-3.90 (m, 1H), 3.15-3.10 (m, 3H), 2.33 (s, 3H), 1.07 (s , 12H). MS: m/z 453.2 (M+H ⁺ ).

Example 17

(6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of tert-butyl methyl((6S)-3-(N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate :

[449] In a solution of (S)-tert-butyl (3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (570 mg, 1.7 mmol) in THF (15 ml), n-BuLi (0.8 ml, 1.9 mmol, 2.5 M in hexanes) was added dropwise at -78°C and the mixture was stirred at this temperature for 1 hour. A solution of TrtNSO (573 mg, 1.9 mmol) in THF (5 ml) was added dropwise and the mixture was stirred at -78°C for 20 minutes before placing in an ice bath. After stirring for a further 10 minutes, tert-butyl hypochlorite (206 mg, 1.9 mmol) was added and the mixture was stirred for 20 minutes. NH ₃ gas was then bubbled through the mixture for 5 minutes and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give tert-butyl methyl ((6S)-3-(N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-6-yl)carbamate (420 mg, yield: 43%) as a yellow solid. MS: m/z 574.5 (M+H ⁺ ).

Step 2 - Synthesis of tert-butyl ((6S)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate:

[450] In solution tert-butyl methyl((6S)-3-(N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl) carbamate (200 mg, 0.3 mmol) in THF (10 ml), MeONa (21 mg, 0.4 mmol) was added and the mixture was stirred for 30 minutes at room temperature. 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (375 mg, 1.7 mmol) was then added. After stirring for 16 hours at room temperature, the mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give tert-butyl ((6S)-3-(N-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6 -yl)(methyl)carbamate (110 mg, yield: 42%) as a white solid.

Step 3 - Synthesis of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 17):

[451] Into a solution of (((6S)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (110 mg, 0.1 mmol) in DCM (5 ml) added two drops of methanesulfonic acid After stirring for 0.5 hour at room temperature, the reaction solution was adjusted to pH=8 with saturated NaHCO ₄ . The mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to obtain the crude product. The crude product was further purified by preparative HPLC (NH ₄ HCO ₃ ) to give ((6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (3.8 mg, yield: 6%, mixture of diastereoisomers) as a white solid substances. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.18 (br. s, 1H), 7.51 (d, J=5.2 Hz, 1H), 7.24 (br. s., 1H). s, 2H), 6.86 (s, 1H), 4.30-4.20 (m, 3H), 3.94 (d, J=12.8 Hz, 1H), 3.15-3.14 (m, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.33 (d, J=2.0 Hz , 3H) 1.96-1.83 (m, 4H). MS: m/z 431.2 (M+H ⁺ ). Example 18

Example 18

(6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of (6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimide amide:

[452] In a solution of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (83 mg, 0. 2 mmol) in THF (3 ml) was added MeONa (28 mg, 0.5 mmol). The reaction mixture was stirred at 45°C for 20 minutes to obtain a sodium salt suspension.

[453] In another flask, a solution of methyl 8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (191 mg, 1.0 mmol) in THF (5 ml) alone Et ₃ N (0.2 ml, 1.1 mmol) and triphosgene (100 mg, 0.4 mmol) were added partly with an ice bath. The reaction mixture was stirred at 70°C for 1 hour under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was added to the above sodium salt suspension. The new reaction mixture was stirred at room temperature for 16 hours and concentrated to give (6S)-N'-(tert-butyldimethylsilyl)-N-((8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (crude), which was directly used in the following stage. MS: m/z 692.4 (M+H ⁺ ).

Step 2 - Synthesis of (6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 18):

[454] Into a solution of (6S)-N'-(tert-butyldimethylsilyl)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (crude) in DCM (2 ml) was added MeSO ₃ H (0.05 ml, 0.88 mmol) at 0°C. After stirring at this temperature for 5 minutes, the reaction solution was adjusted to pH=8 using sat. NaHCO ₃ The resulting mixture was concentrated, diluted with MeCN (3 ml) and filtered. The filtrate was purified by preparative HPLC to give (6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (3 mg, yield: 2%, mixture of diastereoisomers) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (br s, 1H), 7.53 (s, 1H), 7.23 (br s, 1H), 4.59 ( d, J=12.0 Hz, 1H), 4.31-4.17 (m, 3H), 4.03 (s, 1H), 3.36 (overlap, 3H), 2.80 (t, J =6.4 Hz, 4H), 2.72 (t, J=6.0 Hz, 4H), 2.02-1.97 (m, 4H); MS: m/z 450.1 (M+H ⁺ ).

Example 19 and Example 20

(S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazin-3-sulfonidamide and (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[455] In a solution of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (200 mg, 0. 4 mmol) in THF (3 ml) was added MeONa (25 mg, 0.5 mmol) and the mixture was stirred at room temperature for 20 minutes. 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (75 mg, 0.4 mmol) was then added. The resulting mixture was stirred at room temperature for 16 hours, concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-N-((1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide ( 240 mg, yield: 85%) as a yellow solid. MS: m/z 674.5 (M+H ⁺ ).

Step 2 - (S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[456] (S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide: (6S)-N -((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (460 mg, 0.7 mmol) was separated by chiral preparative HPLC to give two isomers (peak 1, 200 mg; peak 2, 227 mg) with unknown absolute stereochemistry at as yellow solids. MS: m/z 674.4 (M+H ⁺ ).

Step 3 - Synthesis of (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 19 and Example 20):

[457] To a solution of the material from peak 1 above (100 mg, 0.2 mmol) in THF (2 ml) was added MeSC ₃ H at 0°C. After stirring at this temperature for 0.5 hours, the reaction mixture was adjusted to pH=8 using sat. _NaHCO3 . The precipitate was collected by filtration, washed with water (2 ml), THF (2 ml) and dried to give (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (27 mg, yield: 42%) as a white solid substances. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.19 (s, 1H), 7.54 (s, 1H), 7.29 (s, 2H), 6.86 (s, 1H) , 4.59 (d, J=12 Hz, 1H), 4.35-4.15 (m, 3H), 4.03 (s, 1H), 3.40 (s, 3H), 2.77 ( t, J=6.8 Hz, 4H), 2.69 (t, J=6.4 Hz, 4H), 2.01-1.88 (m, 4H). MS: m/z 432.2 (M+H ⁺ ).

[458] The material from peak 2 was deprotected and isolated in a similar manner to yield a white solid. (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.16 (s, 1H), 7.51 (s, 1H), 7.18 (s, 2H), 6.85 (s, 1H) , 4.59 (d, J=11.6 Hz, 1H), 4.31-4.15 (m, 3H), 4.03 (s, 1H), 3.36 (s, 3H), 2, 77 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 1.98-1.88 (m, 4H). MS: m/z 432.2 (M+H ⁺ ).

Example 21 and Example 22

(S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide and (R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[459] The title compounds were prepared using the general procedure for the preparation of (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide to obtain a mixture of stereoisomers. (S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide and (R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide was prepared using the general procedure described for the preparation of (S)-N'-((1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and ( R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonidamide (Example 13 and Example 14), replacing 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene with 4-fluoro-8-isocyanato-1, 2,3,5,6,7-hexahydro-s-indacene in step 2. Two isomers with unknown absolute stereochemistry were isolated after purification by chiral preparative HPLC.

[460] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.03 (br s, 1H), 7.45 (br s, 1H), 6.86 (br s, 2H ), 4.36 (t, J=3.6 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.82 (t, J=7.2 Hz, 4H), 2.72 (t, J=7.2 Hz, 4H), 2.20-2.15 (m, 2H), 2.01-1.96 (m, 4H). MS: m/z 420.1 (M+H ⁺ ). Connection 22

[461] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.20 (br s, 1H), 7.50 (s, 1H), 7.23 (s, 2H), 4.40-4.35 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.82 (t, J=7.2 Hz, 4H), 2.72 (t , J=7.2 Hz, 4H), 2.21-2.17 (m, 2H), 2.01-1.96 (m, 4H). MS: m/z 420.1 (M+H ⁺ ). Connection 21

Example 23 and Example 24

(S,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonidamide and (R,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonimidamide

Step 1 - (S,6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonimidamide and (R,6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[462].(6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (280 mg, 0.4 mmol) was separated by chiral preparative HPLC to give two isomers (peak 1, 135 mg; peak 2, 80 mg) with unknown absolute stereochemistry as yellow solids substances; (S,6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide and (R,6S)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonimide amide.

Step 2 - Synthesis of (S,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide and (R,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (example 23 and example 24):

[463] To a solution of the material collected from the above peak 1 (135 mg, 0.2 mmol) in THF (2 ml) was added MeSO ₃ H (6 drops) at 0°C. After stirring at this temperature for 0.5 hour, the reaction mixture was concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give (S,6S)-N'-((4-fluoro-2,6 -diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (40 mg, yield: 46%) as a white solid . Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.01 (s, 1H), 7.52 (m, 1H), 7.33 (s, 2H), 6.86 (s, 1H) , 6.84 (s, 1H), 4.60-4.56 (m, 1H), 4.33-4.18 (m, 3H), 4.04 (s, 1H), 3.36 (s , 3H), 3.20-3.06 (m, 2H), 1.17-1.02 (m, 12H). MS: m/z 454.2 (M+H ⁺ ).

[464] The same was done for peak 2 to obtain a white solid. The material from peak 2 was deprotected and isolated in a similar manner to give (R,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.02 (s, 1H), 7.50 (s, 1H), 7.28 (s, 2H), 6.87 (s, 1H) , 6.84 (s, 1H), 4.60-4.56 (m, 1H), 4.33-4.18 (m, 3H), 4.04 (s, 1H), 3.36 (s , 3H), 3.20-3.06 (m, 2H), 1.17-1.02 (m, 12H). MS: m/z 454.2 (M+H ⁺ ).

Example 25 and Example 26

(R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - tert-butyl ((S)-3-((R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'- tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate and tert-butyl ((S)-3-((S)- N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazin-6-yl)(methyl)carbamate:

[465] tert-butyl ((S)-3-((R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'- tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate and tert-butyl ((S)-3-((S)- N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazin-6-yl)(methyl)carbamate: tert-butyl((6S)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (1.0 g, 1.3 mmol) was separated by chiral preparative HPLC to give two isomers of unknown absolute stereochemistry as white solids (peak 1, 410 mg, yield: 41%; peak 2, 450 mg, yield: 45%).

Step 2 - Synthesis of (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 25 and Example 26):

[466] Methanesulfonic acid (3 drops) was added. To a solution of the material from peak 1 above (200 mg, 0.3 mmol) in DCM (3 ml) was added three drops of methanesulfonic acid. After stirring for 0.5 hours at room temperature, the reaction solution was adjusted to pH=8 using sat. _NaHCO3 . The precipitate was collected by filtration and dried to give (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (17.0 mg, yield: 15%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (br s, 1H), 7.51 (s, 1H), 7.26 (br s, 2H), 6.86 ( s, 1H), 4.36-4.20 (m, 3H), 3.95-3.91 (m, 1H), 3.16-3.15 (m, 1H), 2.77 (t, J=6.8 Hz, 4H), 2.68 (t, J=6.8 Hz, 4H), 2.33 (s, 3H), 2.15 (br s, 1H), 1.96- 1.89 (m, 4H). MS: m/z 431.1 (M+H ⁺ ).

[467] The material from peak 2 above was deprotected and isolated in a similar manner to yield a white solid. (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide. Stereochemistry was randomly assigned to each stereoisomer. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.16 (br s, 1H), 7.51 (s, 1H), 7.23 (br s, 2H), 6.86 ( s, 1H), 4.36-4.20 (m, 3H), 3.95-3.91 (m, 1H), 3.16-3.14 (m, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.69 (t, J=6.8 Hz, 4H), 2.33 (s, 3H), 2.07 (br s, 1H), 1.98- 1.89 (m, 4H). MS: m/z 431.1 (M+H ⁺ ).

Example 27 and Example 28

(R,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide and (S,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonimidamide:

[468] (R,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimide amide and (S,6S) -N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1 -b][l,3]oxazine-3-sulfonidamide (Example 25 and Example 26). After chiral preparative HPLC, two isomers with unknown absolute stereochemistry were isolated as white solids.

[469] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.99 (s, 1H), 7.48 (s, 1H), 7.23 (br s, 2H), 6.86 (s, 1H), 6.84 (s, 1H), 4.33-4.19 (m, 3H), 3.92-3.89 (m, 1H), 3.15-3, 10 (m, 3H), 2.13 (s, 3H), 2.06 (br s, 1H), 1.07 (s, 12H). MS: m/z 453.2 (M+H ⁺ ).

[470] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.03 (s, 1H), 7.50 (s, 1H), 7.23 (s, 2H), 6. 86 (s, 1H), 6.84 (s, 1H), 4.36-4.19 (m, 3H), 3.93-3.86 (m, 1H), 3.11-3.08 ( m, 3H), 2.34 (s, 3H), 2.32 (s, 1H), 0.99 (s, 12H). MS: m/z 453.2 (M+H ⁺ ).

Example 29

N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazol-7- sulfonimidamide

Step 1 - Synthesis of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole:

[471] NBS (3.9 g, 21.8 mmol) was added portionwise to a solution of 2,3-dihydropyrazolo[5,1-b]oxazole (2.0 g, 18.2 mmol) in MeCN (40 ml) at 0°C and stirred the reaction mixture for 2 hours at room temperature. The mixture was filtered and the filtrate was purified using a reverse phase column (MeCN/H ₂ O) to obtain 3 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (2.4 g, yield: 71%) as a white solid.

[0001] ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.30 (s, 1H), 5.12 (t, J=8.0 Hz, 2H), 4.35 (t, J=8 ,0 Hz, 2H).

Steps 2 ~ 4 - Synthesis of N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1- b]oxazole-7-sulfonimidamide (example 29):

[472] These three steps were carried out similarly to the general procedure for the preparation of (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide to give the title compound as a white solid.

[473] N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole -7-sulfonimidamide was prepared as a mixture of enantiomers using the general procedure described for the preparation of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 17), replacing (S)-tert-butyl (3-bromo -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate on 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole at step 1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.06 (br s, H), 7.50 (s, 1H), 7.01 (br s, 2H), 5.17 (t, J=8.4 Hz, 2H), 4.31 (t, J=8.4 Hz, 2H), 2.80 (t, J=7.2 Hz, 4H), 2, 72 (t, J=7.2 Hz, 4H), 1.96-1.89 (m, 4H). MS: m/z 406.1 (M+H ⁺ ).

Example 30

N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b] [1,3]oxazepine-3-sulfonimidamide:

[474] The title compound was prepared using the general procedure for the preparation of (R,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6- methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide to obtain a mixture of stereoisomers. N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b] [1,3]oxazepine-3-sulfonimidamide was prepared as a mixture of enantiomers using the general procedure described for the preparation of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 17), replacing (S)-tert -butyl (3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate on 3-bromo-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine in step 1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.08 (br s, 1H), 7.43 (s , 1H), 6.91 (lat. s, 2H), 4.15 (t, J=5.2 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 2.80 (t, J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.03-1.93 (m, 6H), 1.78-1.71 ( m, 2H). MS: m/z 434.1 (M+H ⁺ ).

Example 31 and Example 32

(R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of (6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimide amide:

[475] In a solution of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (720 mg, 1. 5 mmol) in THF (15 ml) was added MeONa (81 mg, 1.5 mmol). The reaction mixture was stirred at 45°C for 20 minutes to obtain a sodium salt suspension.

[476] A solution of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (crude, - 1.5 mmol) in THF (15 ml) was then added to the above sodium suspension salt. The new reaction mixture was stirred at room temperature for 16 hours and concentrated to give (6S)-N'-(tert-butyldimethylsilyl)-N-((8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (crude), which was directly used in the following stage.

Step 2 - (R,6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N-((8-fluoro-1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide:

[477] (S,6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and R,6S)-N-((8-fluoro-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonimidamide:

[478] (6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-N'-trityl-6 ,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (210 mg, 0.3 mmol) was separated by chiral preparative HPLC to give two isomers with unknown absolute stereochemistry as yellow solids (peak 1, 60 mg; peak 2, 120 mg).

Step 3 - Synthesis of (R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (Example 31 and Example 32):

[479] (S,6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-H-((8-fluoro-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[480] To a solution of the material from peak 1 above (60 mg, 0.09 mmol) in DCM (4 ml) was added MeSO ₃ H (3 drops) at 0°C. After stirring at this temperature for 0.5 hours, the reaction mixture was adjusted to pH=8 using sat. _NaHCO3 . The precipitate was collected by filtration, washed with water (2 ml), DCM (2 ml) and dried to give a white solid (16 mg, yield: 42%). ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.19 (br s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 4.59 (d, J=12.0 Hz, 1H), 4.31-4.17 (m, 3H), 4.03 (s, 1H), 3.34 (overlap, 3H), 2.80 (t, J=6 .4 Hz, 4H), 2.73 (t, J=6.4 Hz, 4H), 2.01-1.97 (m, 4H). MS: m/z 450.1 (M+H ⁺ ).

The material from the above peak 2 was deprotected and isolated in a similar manner to obtain a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.25 (br s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 4.59 (d, J=12.0 Hz, 1H), 4.31-4.17 (m, 3H), 4.03 (s, 1H), 3.34 (overlap, 3H), 2.80 (t, J=6 .4 Hz, 4H), 2.68 (t, J=6.4 Hz, 4H), 2.01-1.97 (m, 4H). MS: m/z 450.1 (M+H ⁺ ).

Example 33 and Example 34

(R,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide:

Step 1 and Step 2 - Synthesis of (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine:

[481] In a solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (5.0 g, 35.7 mmol) and DMAP (44 mg, 0.4 mmol) in pyridine (40 ml) was slowly added Tf ₂ O (20.2 g, 71.4 mmol) at -10°C under N ₂ atmosphere. The mixture was stirred for 2 hours at -10°C. A solution of dimethylamine (20 ml, 33% in water) in MeOH (20 ml) was then added to the mixture and the resulting reaction mixture was stirred for an additional 2 hours at room temperature. The reaction mixture was concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-6-amine (850 mg, yield: 14%) as a yellow solid.

Step 3 - Synthesis of (6S)-6-(dimethylamino)-N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[482] NBS (1.1 g, 6.1 mmol) was added portionwise to a solution of (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-amine (850 mg, 5D mmol) in MeCN (40 ml) at 0°C and stirred the reaction mixture for 2 hours at room temperature. The mixture was filtered and purified using a reverse phase column (MeCN/H ₂ O) to give (S)-3-bromo-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazin-6-amine (770 mg, yield: 59%) as a yellow solid.

Step 4 - Synthesis of (6S)-6-(dimethylamino)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[483] In a solution of (S)-3-bromo-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine (570 mg, 2 .3 mmol) in THF (15 ml), n-BuLi (2.5 M in hexane, 1.0 ml, 2.5 mmol) was added dropwise at -78°C and the mixture was stirred at the same temperature for 1 hour . A solution of TrtNSO (780 mg, 2.6 mmol) in THF (15 ml) was added dropwise and the mixture was stirred at -78°C for 20 minutes before placing in an ice bath at 0°C. After stirring for a further 10 minutes, tert-butyl hypochlorite (278 mg, 2.6 mmol) was added and the mixture was stirred for 20 minutes. The mixture was then bubbled with NH ₃ gas for 5 minutes and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-6-(dimethylamino)-N-trityl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide (330 mg, yield: 30%) as a yellow solid. MS: m/z 488.5 (M+H ⁺ ).

Steps 5~7 - Synthesis of (R,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 33 and Example 34) :

[484] (S,6S)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide: These three steps were carried out similarly to the general procedure for the preparation of (S, 6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide.

[485] (R,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of ( R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 31 and Example 32), replacing ( 6S)-6-methoxy-N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide on (6S)-6-(dimethylamino)-N' -trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and 4-fluoro-8-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene to 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene in step 1. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated as white solids.

[486] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.19 (br s, 1H), 7.52 (s, 1H), 7.28 (s, 2H), 6.86 (s, 1H), 4.45-4.41 (m, 2H), 4.23-4.13 (m, 2H), 2.91-2.87 (m, 1H), 2. 77 (t, J=7.2 Hz, 4H), 2.70-2.67 (m, 4H), 2.26 (s, 6H), 1.98-1.87 (m, 4H). MS: m/z 445.2 (M+H ⁺ ).

[487] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.19 (br s, 1H), 7.52 (s, 1H), 7.25 (s, 2H), 6.86 (s, 1H), 4.45-4.40 (m, 2H), 4.23-4.13 (m, 2H), 2.91-2.87 (m, 1H), 2. 77 (t, J=7.2 Hz, 4H), 2.68 (t, J=7.2 Hz, 4H), 2.27 (s, 6H), 1.93-1.89 (m, 4H ). MS: m/z 445.1 (M+H ⁺ ).

Example 35 and Example 36

(R,6S)-6-((2-fluoroethyl)amino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)-N'-((1,2, 3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide

Step 1 - Synthesis of tert-butyl (S)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(2-fluoroethyl)carbamate:

[488] In a solution of (S)-tert-butyl (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (5.0 g, 20.9 mmol) in DMF (30 ml) was added portionwise NaH (60% in mineral oil, 1.0 g, 25.1 mmol) at 0°C under N ₂ atmosphere. The mixture was stirred at 0°C for 30 minutes. 1-Bromo-2-fluoroethane (3.2 g, 25.1 mmol) was then added dropwise at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was poured into water (120 ml) and extracted with EtOAc (100 ml x 3). The combined organic layer was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ and concentrated. The residue was purified using a silica flash column (PE/EtOAc) to give (S)-tert-butyl (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl) (2-fluoroethyl)carbamate (4.0 g, yield: 66%) as a white solid.

Steps 2~6 - Synthesis of (R,6S)-6-((2-fluoroethyl)amino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide (example 35 and example 36):

[489] (R,6S)-6-((2-fluoroethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)-N-((1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide: These five steps were carried out similarly to the general procedure for the preparation of (S,6S)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide.

[490] (R,6S)-6-((2-fluoroethyl)amino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)-N'-((1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (example 33 and example 34), replacing (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine with tert-butyl (S)-( 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(2-fluoroethyl)carbamate in step 2. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated.

[491] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (br s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 6.85 (s, 1H), 4.52 (t, J=4.8 Hz, 1H), 4.40-4.37 (m, 2H), 4.27-4.20 (m, 2H) , 3.94 (dd, J=12.0, 5.2 Hz, 1H), 3.34 (overlap, 1H), 2.97-2.93 (m, 1H), 2.90-2.86 (m, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.29-2.26 (m, 1H) , 1.97-1.89 (m, 4H). MS: m/z 463.1 (M+H ⁺ ).

[492] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (br s, 1H), 7.52 (s, 1H), 7.24 (s, 2H), 6.85 (s, 1H), 4.52 (t, J=4.8 Hz, 1H), 4.41-4.367 (m, 2H), 4.27-4.23 (m, 2H), 3 .94 (dd, J=12.0, 5.2 Hz, 1H), 3.34 (overlap, 1H), 2.95 (t, J=5.2 Hz, 1H), 2.89 (t, J=5.2 Hz, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.33-2.31 ( m, 1H), 1.97-1.89 (m, 4H). MS: m/z 463.1 (M+H ⁺ ).

Example 37

8-(3-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)ureido)-1,2,3,5,6,7-hexahydro- s-indacene-4-carboxylic acid

Step 1 - Synthesis of 8-bromo-1,2,3,5,6,7-hexahydro-s-indacene-4-amine:

[493] To a solution of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (500 mg, 2.9 mmol) in DCM (15 ml) was added portionwise NBS (530 mg, 3. 0 mmol) at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with DCM (50 ml), washed with H ₂ O (40 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using a silica flash column (0%~20% EtOAc in PE) to give 8-bromo-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (570 mg, yield : 78%) as a red solid. ^1H NMR (400 MHz, CDCl ₃ ): δ = 3.44 (br s, 2H), 2.90 (t, J=7.2 Hz, 4H), 2.79 (t, J=7, 2 Hz, 4H), 2.17-2.09 (m, 4H).

Step 2 - Synthesis of methyl 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate:

[494] Mixture of 8-bromo-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (570 mg, 2.3 mmol), TEA (460 mg, 4.5 mmol) and Pd(dppf)Cl ₂ (160 mg, 0.2 mmol) in MeOH (25 ml) was stirred for 16 hours at 75°C in a CO atmosphere (balloon). The reaction mixture was concentrated and purified using a silica flash column (0%~20% EtOAc in PE) to give methyl 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate ( 410 mg, yield: 78%) as a red solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 3.82 (s, 5H), 3.22 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz , 4H), 2.16-2.07 (m, 4H).

Step 3 - Synthesis of methyl 8-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)ureido)-1,2,3 ,5,6,7-hexahydro-s-indacene-4-carboxylate:

[495] In a solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (300 mg, 0.7 mmol) in THF (15 ml ) MeONa (41 mg, 0.8 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes to obtain a sodium salt suspension.

[496] In another flask, a solution of methyl 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate (157 mg, 0.7 mmol) in THF (15 ml) alone Triethylamine (137 mg, 1.4 mmol) and triphosgene (62 mg, 0.2 mmol) were partly added at 0°C. After stirring at room temperature for 10 minutes under N ₂ atmosphere, the reaction mixture was filtered. The filtrate was added to the above sodium salt suspension. The new reaction mixture was stirred at room temperature for 16 hours, then concentrated and purified using a reverse phase column (MeCN/H ₂ O) to give methyl 8-(3-(N-trityl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl)ureido)-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate (310 mg, yield: 65 %) as a white solid.

Step 4 - Synthesis of 8-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl)ureido)-1,2,3, 5,6,7-hexahydro-s-indacene-4-carboxylic acid:

[497] In a solution of methyl 8-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)ureido)-1,2, 3,5,6,7-hexahydro-s-indacene-4-carboxylate (200 mg, 0.3 mmol) in DMSO (5 ml) was added t-BuOK (160 mg, 1.4 mmol). After stirring at room temperature for 16 hours, the reaction mixture was poured into H ₂ O (20 ml), acidified to pH=6 with 2 M aq. HCl and extracted with EtOAc (15 ml x 2). The combined EtOAc was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated to give 8-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonimidoyl)ureido)-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylic acid (190 mg, crude) as a white solid. MS: m/z 688.6 (M+H ⁺ ).

Stage 5 Synthesis of 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-λ ⁶ -sulfaneylidene)ureido)- 1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylic acid (example 37):

[498] In a solution of 8-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl)ureido)-1,2,3 ,5,6,7-hexahydro-s-indacene-4-carboxylic acid (190 mg, crude) in DCM (5 ml) was added two drops of MeSO ₃ H at room temperature. After stirring at this temperature for 5 minutes, the reaction solution was poured into H ₂ O (15 ml) and acidified to pH=8 with sat. _NaHCO3 . The resulting solution was washed with DCM (10 ml x 2) and the aqueous phase was acidified to pH=6 with 2 M aq. HCl. The precipitate was collected by filtration and then purified by preparative HPLC (PHP) to give 8-(3-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl) ureido)-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylic acid (26 mg, yield: 20%, mixture of stereoisomers) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 12.46 (br s, 1H), 8.39 (s, 1H), 7.52 (s, 1H), 7.25 (s, 2H), 4.44-4.39 (m, 2H), 4.11 (t, J=6.0 Hz, 2H), 3.05 (t, J=7.2 Hz, 4H), 2, 71 (t, J=7.2 Hz, 4H), 2.20-2.15 (m, 2H), 1.96-1.89 (m, 4H). MS: m/z 446.1 (M+H ⁺ ).

Example 38 and Example 39

(R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 - Synthesis of (S)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine:

[499] (S)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine was prepared in the same way as (S )-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine, replacing 3-methoxyazetidine with dimethylamine.

Step 2 - Synthesis of (S)-3-bromo-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine:

[500] In a solution of (S)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (335 mg, 1.6 mmol) in DCM (5 ml), NBS (300 mg, 1.7 mmol) was added portionwise and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM (15 ml) and washed with sat. NaHCO ₃ (15 ml). The organic layer was dried with Na ₂ SO ₄ and concentrated to dryness to give (S)-3-bromo-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine (440 mg, yield: 95%) as a yellow solid. MS: m/z 290.3 (M+H ⁺ ).

Step 3 - Synthesis of (6S)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonimidamide:

[501] In a solution of (S)-3-bromo-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (440 mg , 1.5 mmol) in THF (5 ml), n-BuLi (0.6 ml, 1.5 mmol, 2.5 M in hexane) was added dropwise at -78°C and the mixture was stirred at this temperature for 30 min. A solution of TrtNSO (466 mg, 1.5 mmol) in THF (2 ml) was added dropwise and the mixture was stirred at -78°C for 20 minutes before placing in an ice bath. After stirring for a further 10 minutes, tert-butyl hypochlorite (181 mg, 1.7 mmol) was added and the mixture was stirred for 20 minutes. NH ₃ gas was then bubbled through the mixture for 5 minutes and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture was quenched with H ₂ O (1 ml) and concentrated to dryness. The residue was purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide (336 mg, yield: 35%) as a white solid. MS: m/z 530.5 (M+H ⁺ ).

Step 4 - Synthesis of (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-N '-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[502] Into a solution of (6S)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide (276 mg, 0.5 mmol) in THF (10 ml), MeONa (42 mg, 0.8 mmol) was added and the mixture was stirred for 30 minutes at room temperature. 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (104 mg, 0.5 mmol) was then added and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to give (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (283 mg, yield: 60%) as a white solid. MS: m/z 729.6 (M+H ⁺ ).

Step 5 - (S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)- N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N-((1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonimidamide:

[503] (6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-N' -Trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (330 mg) was separated by chiral preparative HPLC to give two isomers of unknown absolute stereochemistry as white solids (peak 1, 132 mg, yield: 40%; peak 2, 171 mg, yield: 51%).

Step 6 - Synthesis of (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl) )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((l,2,3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide (example 38 and example 39):

[504] To a solution of the material from peak 1 above (132 mg, 0.2 mmol) in DCM (3 ml) was added two drops of methanesulfonic acid. After stirring at room temperature for 10 minutes, the reaction solution was adjusted to pH=8 using sat. _NaHCO3 . The resulting mixture was concentrated to dryness and purified using a reverse phase column (MeCN/H ₂ O) to obtain (72 mg, yield: 83%) as a white solid (one unknown stereoisomer). ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (br s, 1H), 7.51 (s, 1H), 7.28 (s, 2H), 6.86 (s, 1H), 4.35-4.22 (m, 2H), 4.14 (dd, J=13.2, 4.4 Hz, 1H), 3.94-3.90 (m, 1H), 3 .85 (d, J=13.2 Hz, 1H), 3.53 (t, J=6.4 Hz, 2H), 3.14 (s, 3H), 3.02-2.95(m, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 1.97-1.89 (m, 4H). MS: m/z 487.2 (M+H ⁺ ).

[505] The material from the above peak 2 was deprotected and isolated in a similar manner to give a white solid (one unknown stereoisomer) (72 mg, yield: 63%). ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.17 (br s, 1H), 7.48 (s, 1H), 7.24 (s, 2H), 6.86 (s, 1H), 4.30-4.20 (m, 2H), 4.14 (dd, J=12.8, 4.0 Hz, 1H), 3.96-3.90 (m, 1H), 3 .85 (d, J=12.8 Hz, 1H), 3.57-3.52 (m, 2H), 3.14 (s, 3H), 3.02-2.95 (m, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H): 1.97-1.90 (m, 4H). MS: m/z 487.2 (M+H ⁺ ).

Example 40 and Example 41

(R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide:

[506] (R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (example 31 and example 32), replacing (6S)-6-methoxy-N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide with tert-butyl methyl ((6S)-3-(N'-Tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate in step 1. After preparative HPLC, the two isomers of unknown absolute stereochemistry as white solids.

[507] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.20 (br s, 1H), 7.50 (s, 1H), 7.24 (s, 2H), 4.35-4.20 (m, 3H), 3.95-3.91 (m, 1H), 3.15-3.14 (m, 1H), 2.81 (t, J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.33 (s, 3H) 2.03-1.96 (m, 4H). MS: m/z 449.1 (M+H ⁺ ).

[508] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.18 (br s, 1H), 7.51 (s, 1H), 7.24 (s, 2H), 4.36-4.20 (m, 3H), 3.93 (dd, J=12.4, 4.0 Hz, 1H), 3.16-3.15 (m, 1H), 2.81 ( t, J=7.6 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.33 (s, 3H) 2.03-1.96 (m, 4H). MS: m/z 449.1 (M+H ⁺ ).

Example 42 and Example 43

(S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N-((8-fluoro-1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonimidamide:

[509] (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin- 1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N'-((8-fluoro-1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-( (8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 31 and Example 32), replacing (6S)-6-methoxy-N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonimidamide on (6S)-6-(3-methoxyazetidin-1-yl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonidamide in step 1. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated.

[510] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.20 (br s, 1H), 7.51 (s, 1H), 7.28 (s, 2H), 4.27-4.17(m, 2H), 4.15-4.12 (m, 1H), 3.93-3.83 (m, 2H), 3.54-3.51 (m, 2H ), 3.14 (s, 3H), 3.02-2.96 (m, 3H), 2.80 (t, J=7.6 Hz, 4H), 2.75-2.50 (m, 4H), 2.03-1.96 (m, 4H). MS: m/z 505.1 (M+H ⁺ ). Connection 43

[511] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.12 (br s, 1H), 7.47 (s, 1H), 7.12 (s, 2H), 4.27-4.19(m, 3H), 3.94-3.83 (m, 2H), 3.56-3.51 (m, 2H), 3.14 (s, 3H), 3. 02-2.96 (m, 3H), 2.80 (t, J=7.2 Hz, 4H), 2.74 (t, J=7.2 Hz, 4H), 2.03-1.96 (m, 4H). MS: m/z 505.2 (M+H ⁺ ). Connection 42

Example 44 and Example 45

(R,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (8,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3, 5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide:

Step 1 - Synthesis of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl trifluoromethanesulfonate:

[512] Tf ₂ O (40.4 g, 142.8 mmol) was added dropwise to the solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6 -ol (10.0 g, 71.4 mmol) and DMAP (88 mg, 0.7 mmol) in pyridine/DCM (20 ml/80 ml) at -10°C under N ₂ atmosphere. After 2 hours, the mixture was purified using a silica column (PE/EtOAc = 3/1) to give (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl trifluoromethanesulfonate (12.1 g, yield: 62%) as a yellow oil.

Step 2 - Synthesis of (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine:

[513] A solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl trifluoromethanesulfonate (12.1 g, 44.5 mmol) and dimethylamine (33 % in water, 20 ml) in MeOH (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the crude residue was purified using a reverse phase column (0~60% MeCN in H ₂ O) to give (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazin-6-amine (1.1 g, yield: 15%) as a yellow solid.

Step 3 - Synthesis of (S)-3-bromo-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine:

[514] NBS (1.7 g, 11.2 mmol) was added portionwise to a solution of (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-6-amine (1.7 g, 10.2 mmol) in MeCN (40 ml) at 0°C at room temperature. After 2 hours, the reaction was filtered and the filtrate was purified using a reverse phase column (5% ~ 95% MeCN in _H2O ) to give (S)-3-bromo-N,N-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-6-amine (1.9 g, yield: 76%) as a yellow solid.

Step 4 - Synthesis of (6S)-6-(dimethylamino)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimide amide:

[515] n-BuLi (2.5 M in hexane, 3.0 ml, 7.4 mmol) was added dropwise to a solution of (S)-3-bromo-N,N-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-6-amine (1.4 g, 5.7 mmol) in THF (15 ml) at -78°C. After 1 hour, a solution of TrtNSO (2.3 g, 7.4 mmol) in THF (10 ml) was added dropwise. The reaction mixture was left to stir for 20 minutes and then placed in an ice bath at 0°C. After stirring for an additional 10 minutes, tert-butyl hypochlorite (807 mg, 7.4 mmol) was added. The reaction mixture was stirred for 20 minutes, then NH ₃ gas was bubbled through the mixture for 5 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated to dryness and the crude residue was purified using a reverse phase column (5% ~ 95% MeCN in H ₂ O) to give (6S)-6-(dimethylamino)-N'-trityl-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (1.1 g, yield: 39%) as a yellow solid. MS: m/z 488.6 (M+H).

Step 5 - Synthesis of (6S)-6-(dimethylamino)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'- trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[516] MeONa (73 mg, 1.4 mmol) was added to a solution of (6S)-6-(dimethylamino)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonidamide (600 mg, 1.2 mmol) in THF (10 ml) at room temperature. After 5 minutes, the reaction mixture was heated at 45°C for 20 minutes to obtain a sodium salt suspension. The reaction mixture was cooled to room temperature and a solution of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-indacene (crude, ~1.4 mmol) in THF (15 ml) was added. After 16 hours, the reaction mixture was concentrated and the crude residue was purified using a reverse phase column (5% ~ 95% MeCN in H ₂ O) to give (6S)-6-(dimethylamino)-N-((8-fluoro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonidamide (450 mg, yield: 52%) as a yellow solid. MS m/z 705.7 (M+H ⁺ ).

Step 6 - (S,6S)-6-(dimethylamino)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N' -trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-6-(dimethylamino)-N-((8-fluoro- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonimidamide:

[517] (6S)-6-(dimethylamino)-N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (450 mg, 0.6 mmol) was separated by chiral preparative HPLC to give two isomers with unknown absolute stereochemistry as white solids (peak 1, 160 mg; peak 2, 210 mg).

Step 7 - Synthesis of (R,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide ( example 44 and example 45):

[518] Methanesulfonic acid (3 drops) was added to a solution of material from peak 1 (160 mg, 0.2 mmol) in DCM (4 ml) at 0°C. After 30 minutes, the reaction mixture was adjusted to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The resulting precipitate was collected by filtration, washed with water (2 ml), DCM (2 ml) and dried to give (R,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (68 mg, yield: 64%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.17 (br s, 1H), 7.52 (s, 1H), 7.27 (s, 2H), 4.45-4, 41 (m, 2H), 4.24-4.13 (m, 2H), 2.91-2.87 (m, 1H), 2.80 (t, J=7.6 Hz, 4H), 2 .70-2.66 (m, 4H), 2.26 (s, 6H), 2.03-1.95 (m, 4H). MS: m/z 463.1 (M+H ⁺ ).

[519] The material from peak 2 was deprotected and isolated in a similar manner to give (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.12 (br s, 1H), 7.50 (s, 1H), 7.15 (s, 2H), 4.44-4, 42 (m, 2H), 4.25-4.13 (m, 2H), 2.90-2.88 (m, 1H), 2.80 (t, J=7.6 Hz, 4H), 2 .73 (t, J=7.6 Hz, 4H), 2.29 (s, 6H), 2.03-1.96 (m, 4H). MS: m/z 463.1 (M+H ⁺ ).

Example 46 and Example 47

(R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-fluoroethyl)amino) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-fluoroethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazine-3-sulfonimidamide:

[520] (R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-fluoroethyl )amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((8-fluoro-1,2, 3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-fluoroethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (S,6S)-6-(dimethylamino )-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide (Example 44 and Example 45), replacing (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazin-6-amine to tert-butyl (S)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(2-fluoroethyl)carbamate to step 3. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated.

[521] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.21(br s, 1H), 7.57(s, 1H), 7.23(s, 2H), 4.70-4.21 (m, 7H), 2.83-2.62 (m, 10H), 2.04-1.97 (m, 5H). MS: m/z 481.1 (M+H ⁺ ).

[522] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.22 (br s, 1H), 7.61 (s, 1H), 7.32 (s, 2H), 4.72-4.45 (m, 5H), 4.28-4.22 (m, 1H), 3.95-3.92 (m, 1H), 2.83-2.67 (m, 10H ), 2.08-1.97 (m, 5H). MS: m/z 481.1 (M+H ⁺ ).

Example 48 and Example 49

(R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-sulfonimidamide and (S,6S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(3-methoxyazetidine -1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[523] (R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide and (8,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6- (3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide was prepared using the general procedure described for the preparation of (R,6S) -N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 38 and Example 39) , replacing 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene with 3-isocyanato-2,4-diisopropyl-6-methoxypyridine in step 4. After preparative HPLC, two isomers with unknown absolute stereochemistry.

[524] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.02 (s, 1H), 7.51 (s, 1H), 7.33 (s, 2H), 6. 45 (s, 1H), 4.26-4.20 (m, 2H), 4.13 (dd, J=12.8, 4.0 Hz, 1H), 3.96-3.91 (m, 1H), 3.88-3.83 (m, 1H), 3.81 (s, 3H), 3.57-3.51 (m, 2H), 3.20-3.18 (m, 1H) , 3.15 (s, 3H), 3.03-2.97 (m, 4H), 1.18-1.06 (m, 12H). MS: m/z 522.2 (M+H ⁺ ).

[525] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.00 (s, 1H), 7.47 (s, 1H), 7.26 (s, 2H), 6. 45 (s, 1H), 4.30-4.28 (m, 1H), 4.20-4.10 (m, 2H), 3.96-3.91 (m, 1H), 3.88- 3.85 (m, 1H), 3.81 (s, 3H), 3.58-3.52 (m, 2H), 3.20-3.18 (m, 1H), 3.15 (s, 3H), 3.03-2.97 (m, 4H), 1.18-1.06 (m, 12H). MS: m/z 522.2 (M+H ⁺ ).

Example 50 and Example 51

(R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-3-sulfonidamide and (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of tert-butyl ((6S)-3-(N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate:

[526] MeONa (81 mg, 1.5 mmol) was added to a solution of tert-butyl methyl ((6S)-3-(N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-6-yl)carbamate (573 mg, 1.0 mmol) in THF (10 ml) at room temperature. After 30 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (234 mg, 1.0 mmol) was added and the mixture was stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified using a reverse phase column (5 ~ 95% MeCN in H ₂ O) to give tert-butyl ((6S)-3-(N-((2,4-diisopropyl-6- methoxypyridin-3-yl)carbamoyl)-N-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (500 mg, yield : 62%) as a yellow solid.

Step 2 - tert-butyl ((S)-3-((S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate and tert-butyl ((S)-3-((R)-N-((2,4- diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate :

[527] tert-butyl ((6S)-3-(N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][l,3]oxazin-6-yl)(methyl)carbamate (500 mg, 0.6 mmol) was separated by chiral preparative HPLC to give two isomers of unknown absolute stereochemistry as white solids (peak 1, 201 mg, yield: 40%; peak 2, 200 mg, yield: 44%).

Step 3 - Synthesis of (R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazin-3-sulfonidamide and (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 50 and Example 51):

[528] Methanesulfonic acid (5 drops) was added to a solution of material from peak 1 (200 mg, 0.25 mmol) in DCM (5 ml) at room temperature. After 30 minutes, the reaction mixture was adjusted to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The reaction mixture was concentrated and the crude residue was purified using a reverse phase column (0 ~ 95% MeCN in H ₂ O) to obtain the crude product. The crude material was further purified by preparative HPLC (NH ₄ HCO ₃ ) to give (R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (60 mg, yield: 52%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 7.99 (s, 1H), 7.49 (s, 1H), 7.25 (s, 2H), 6.45 (s, 1H) , 4.32-4.20 (m, 3H), 3.93 (dd, J=12.4, 4.4 Hz, 1H), 3.80 (s, 3H), 3.21-3.16 (m, 2H), 3.05-2.98 (m, 1H), 2.35(s, 3H), 1.10-1.06 (m, 12H). MS: m/z 466.1 (M+H ⁺ ).

[529] Methanesulfonic acid (2 drops) was added to a solution of material from peak 2 (171 mg, 0.24 mmol) in DCM (4 ml) at room temperature. After 10 minutes, the reaction mixture was brought to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The precipitate was collected by filtration and dried to give (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (86 mg, yield: 67%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.02 (s, 1H), 7.51 (s, 1H), 7.27 (s, 2H), 6.45 (s, 1H) , 4.37-4.20 (m, 3H), 3.93 (dd, J=12.4, 4.8 Hz, 1H), 3.80 (s, 3H), 3.21-3.16 (m, 2H), 3.05-2.97 (m, 1H), 2.35 (s, 3H), 1.10-1.06 (m, 12H). MS: m/z 466.2 (M+H ⁺ ).

Example 52 and Example 53

(R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazin-3-sulfonidamide and (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[530] n-BuLi (2.5 M in hexane, 1.5 ml, 3.8 mmol) was added dropwise to a solution of (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine (900 mg, 3.8 mmol) in THF (18 ml) at -78°C. After 30 minutes, a solution of TrtNSO (1.2 g, 3.8 mmol) in THF (5 ml) was added dropwise. The reaction mixture was left to stir for 30 minutes and then placed in an ice bath at 0°C. After stirring for an additional 10 minutes, tert-butyl hypochlorite (453 mg, 4.2 mmol) was added. The reaction mixture was stirred for 20 minutes, then NH ₃ gas was bubbled through the mixture for 5 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated to dryness and the crude residue was purified using a reverse phase column (0 ~ 95% MeCN in H ₂ O) to give (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (800 mg, yield: 44%) as a yellow solid. MS: m/z 475.5 (M+H ⁺ ).

Step 2 - Synthesis of (6S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo [5, 1 -b][1,3]oxazine-3-sulfonimidamide:

[531] MeONa (43 mg, 0.8 mmol) was added to a solution of (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazine-3-sulfonidamide (250 mg, 0.5 mmol) in THF (10 ml) at room temperature. After stirring for 20 minutes, a suspension of sodium salt was formed.

[532] In a separate flask, triphosgene (98 mg, 0.3 mmol) was added in one part to a solution of 2,4-diisopropyl-6-methoxypyridin-3-amine (208 mg, 1.0 mmol) and triethylamine (152 mg, 1 .5 mmol) in THF (10 ml) at 0°C in an atmosphere of N ₂ . After 5 minutes, the reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was filtered and the filtrate was added to the sodium salt suspension. After 16 hours, the reaction mixture was concentrated and the crude residue was purified using a reverse phase column (5 ~ 95% MeCN in H ₂ O) to give (6S)-N-((2,4-diisopropyl-6-methoxypyridine-3- yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (244 mg, yield: 65%) in as a yellow solid. MS: m/z 709.7 (M+H ⁺ ).

Step 3 - (8,6S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-sulfonimidamide and (R,6S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-N-trityl -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[533] (6S)-N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (244 mg, 0.3 mmol) was separated by chiral preparative HPLC to give two isomers of unknown absolute stereochemistry as yellow solids (peak 1, 140 mg; peak 2 , 120 mg).

Step 4 - Synthesis of (R,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-3-sulfonidamide and (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 52 and Example 53):

[534] Methanesulfonic acid (6 drops) was added to a solution of material from peak 1 (140 mg, 0.2 mmol) in THF (2 ml) at 0°C. After 30 minutes, the reaction mixture was adjusted to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The reaction mixture was concentrated and the crude residue was purified using a reverse phase column (0 ~ 95% MeCN in H ₂ 0) to give (R,6S)-N'-((2,4-diisopropyl-6-methoxypyridine-3- yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (63 mg, yield: 68%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.06 (s, 1H), 7.56 (s, 1H), 7.35 (s, 2H), 6.48 (s, 1H) , 4.64-4.60 (m, 1H), 4.33-4.22 (m, 3H), 4.07 (s, 1H), 3.84 (s, 3H), 3.39 (s , 3H), 3.24-3.19 (m, 1H), 3.06-3.01 (m, 1H), 1.22-1.09 (m, 12H). MS: m/z 467.1 (M+H ⁺ ).

[535] The material from peak 2 was deprotected and isolated in a similar manner to give (S,6S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6-methoxy-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.06 (s, 1H), 7.53 (s, 1H), 7.32 (s, 2H), 6.48 (s, 1H) , 4.66-4.62 (m, 1H), 4.30-4.21 (m, 3H), 4.08-4.05 (m, 1H), 3.84 (s, 3H), 3 .40 (s, 3H), 3.27-3.18 (m, 1H), 3.09-3.02 (m, 1H), 1.17-1.09 (m, 12H). MS: m/z 467.1 (M+H ⁺ ).

Example 54 and Example 55

(R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-methoxyethyl)amino)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6-((2-methoxyethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[536] (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-methoxyethyl)amino)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-((2-methoxyethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-6-((2-fluoroethyl)amino)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)- N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide (Example 35 and Example 36), replacing 1-bromo-2-fluoroethane with 1-bromo-2-methoxyethane in step 1. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated.

[537] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.17 (br s, 1H), 7.51 (s, 1H), 7.24 (s, 2H), 6.86 (s, 1H), 4.39 (dd, J=11.6, 2.8 Hz, 1H), 4.24 (dd, J=12.0, 5.2 Hz, 2H), 3 .95 (dd, J=12.4, 5.2 Hz, 1H), 3.37 (t, J=5.6 Hz, 2H), 3.31 (overlap, 1H), 3.23 (s, 3H), 2.77 (t, J=7.2 Hz, 6H), 2.70 (t, J=7.2 Hz, 4H), 2.09-2.01 (m, 1H), 2, 00-1.89 (m, 4H). MS: m/z 475.1 (M+H ⁺ ).

[538] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (br s, 1H), 7.52 (s, 1H), 7.24 (s, 2H), 6.86 (s, 1H), 4.39 (dd, J=9.6, 2.0 Hz, 1H), 4.25-4.19 (m, 2H), 3.94 (dd, J= 12.0, 4.8 Hz, 1H), 3.37 (t, J=5.6 Hz, 2H), 3.31 (overlap, 1H), 3.23 (s, 3H), 2.77 ( t, J=5.6 Hz, 6H), 2.70 (t, J=7.2 Hz, 4H), 2.10-2.00 (m, 1H), 1.97-1.89 (m , 4H). MS: m/z 475.1 (M+H ⁺ ).

Example 56 and Example 57

(R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

Step 1 - Synthesis of tert-butyl (S)-(2-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)oxy)ethyl)(methyl) carbamate:

[539] In a solution of (S)-2-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)oxy)-N-methylethanamine (900 mg, 4.6 mmol) in dioxane (8 ml) a solution of NaOH (910 mg, 22.8 mmol) in H ₂ O (8 ml) and BoC ₂ O (1.1 g, 5.0 mmol) was added at 0°C . After 5 minutes, the reaction mixture was warmed to room temperature and stirred for another 3 hours. The reaction mixture was diluted with H ₂ O (30 ml) and extracted with EtOAc (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated, and the crude residue was purified using a silica gel column (PE/EtOAc = 1/2 to 100% EtOAc) to give tert-butyl (S)-(2-((6.7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)oxy)ethyl)(methyl)carbamate (1.0 g, yield: 79%) as a colorless oil. MS: m/z 298.4 (M+H ⁺ ).

Step 2 ~ 6 - (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide (example 56 and example 57):

[540] (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-(methylamino)ethoxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-6-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-(dimethylamino)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (example 33 and example 34), replacing (S)-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine with tert-butyl (S)-( 2-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)oxy)ethyl)(methyl)carbamate in step 2. After preparative HPLC, two isomers were isolated with unknown absolute stereochemistry.

[541] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.17 (br s, 1H), 7.54 (s, 1H), 6.86 (s, 1H), 4.58-4.54 (m, 1H), 4.32-4.24 (m, 2H), 4.19-4.15 (m, 2H), 3.65-3.59 (m, 2H ), 2.78 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 2.60-2.58 (m, 2H), 2.25 (s, 3H), 1.97-1.90 (m, 4H). MS: m/z 475.1 (M+H ⁺ ).

[542] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.15 (br s, 1H), 7.52 (s, 1H), 6.85 (s, 1H), 4.58-4.54 (m, 1H), 4.29-4.25 (m, 2H), 4.19-4.15 (m, 2H), 3.62-3.59 (m, 2H ), 2.78 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.58 (t, J=5.6 Hz, 2H), 2.24 (s, 3H), 1.97-1.90 (m, 4H). MS: m/z 475.1 (M+H ⁺ ).

Example 58 and Example 59

(R,6S)-6-amino-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-amino-N'-((1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[543] (R,6S)-6-amino-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-amino-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S) -6-((2-fluoroethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide and (S,6S)-6-((2-fluoroethyl)amino)-N-((1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 35 and Example 36), replacing 1 -bromo-2-fluoroethane to bromine(methoxy)methane in step 1. After preparative HPLC, two isomers with unknown absolute stereochemistry were isolated.

[544] Peak 1: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.19 (br s, 1H), 7.52 (br s, 1H), 7.25 (br s, 2H ), 6.86 (s, 1H), 4.32 (dd, J=10.8, 2.4 Hz, 1H), 4.21 (dd, J=12.8, 4.8 Hz, 1H) , 4.04-4.00 (m, 1H), 3.79-3.74 (m, 1H), 3.45-3.40 (m, 1H), 2.79 (t, J=7, 2 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.32-1.89 (m, 4H). MS: m/z 417.1 (M+H ⁺ ).

[545] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (br s, 1H), 7.52 (br s, 1H), 7.24 (br s, 2H ), 6.86 (s, 1H), 4.30 (d, J=5.6 Hz, 1H), 4.21 (dd, J=12.0, 4.4 Hz, 1H), 4.04 -4.00 (m, 1H), 3.77 (dd, J=12.0, 6.0 Hz, 1H), 3.47-3.40 (m, 1H), 2.77 (t, J =6.8 Hz, 4H), 2.70 (t, J=7.2 Hz, 4H), 2.07-1.91 (m, 4H). MS: m/z 417.1 (M+H ⁺ ).

Example 60

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3- sulfonimidamide:

Step 1 - Synthesis of N-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfinamide:

[546] n-BuLi (2.5 M in hexane, 0.72 ml, 1.79 mmol) was added dropwise to a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (300 mg, 1.49 mmol) in anhydrous THF (2 ml) at -78°C. After 1 hour, a solution of TrtNSO (547 mg, 1.79 mmol) in THF (2 ml) was added dropwise. The reaction mixture was left to stir for 25 minutes and then placed in an ice bath at 0°C. After 20 minutes, water (20 ml) was added. The mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , concentrated, and the crude residue was purified by silica chromatography (EtOAc/hexane 0 to 100%) to give N-trityl-4,5,6, 7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfinamide (130 mg, 20.4%) as a white solid. LCMS: m/z 428 (M+H ⁺ ).

Step 2 - Synthesis of N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide:

[547] tert-butyl hydroxyperoxide (38 μL, 0.395 mmol) was added to a solution of N-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfinamide (130 mg, 0.304 mmol) in THF (1 ml) at 0°C. After 1 hour, (1 M in THF, 1.3 ml) was added. The reaction mixture was warmed to room temperature and left stirring for an additional 3 hours. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (3×15 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide (135 mg, 100%) as a white solid, which was used in the next step without further purification.

Step 3-4 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-3-sulfonimidamide (example 60):

[548] NaH (60% in mineral oil, 18 mg, 0.458 mmol) was added to a solution of N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonidamide (135 mg, 0.305 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (60.8 mg, 0.305 mmol) in THF (2 ml) at 0°C. After 5 minutes, the reaction mixture was warmed to room temperature and stirred for another 1 hour. MeOH (5 mL) was added and the solvent was removed under reduced pressure to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-trityl-4,5 ,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide, which was used in the next step without further purification.

[549] The crude material was dissolved in anhydrous DCM (2 mL) and methanesulfonic acid (58.6 mg, 39.6 μL, 0.610 mmol) was added dropwise at 0°C. After 30 minutes, toluene (10 ml) was added and the solvent was removed under reduced pressure. The crude residue was dissolved in MeOH and purified by preparative HPLC to give N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7 -tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide (16 mg, yield: 13% as a mixture of enantiomers) as white solids. LCMS: m/z 400 (M+H ⁺ ).

Example 61 and Example 62

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7,8-dihydro-4H,6H-pyrazolo[5,1- c][1,4]oxazepine-3-sulfonimidamide and (R)-N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7,8 -dihydro-4H,6H-pyrazolo[5,1-c][1,4]oxazepine-3-sulfonimidamide:

Step 1 Synthesis of ethyl 1-(3-hydroxypropyl)-1H-pyrazole-5-carboxylate:

[550] To a solution of ethyl 1H-pyrazole-5-carboxylate (5.0 g, 35.7 mmol) in DMF (35 ml) was added 3-bromo-1-propanol (9.9 g, 71.3 mmol) and K ₂ CO ₃ (14.8 g, 107 mmol). The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-35% EtOAc in petroleum ether) to give ethyl 1-(3-hydroxypropyl)-1H-pyrazole-5-carboxylate (4 g, yield: 56%) as a colorless oil. The regio isomer was drained during purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.49 (d, J=1.6 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 4.71 (t, J=6.4 Hz, 2H), 4.34 (k, J=7.2 Hz, 2H), 3.55-3.49 (m, 2H), 2.11-2.04 (m, 2H ), 1.42-1.31 (m, 1H), 1.37 (t, J=6.8 Hz, 3H). MS: m/z 198.9 (M+H ⁺ ).

Step 2 - Synthesis of 3-(5-(hydroxymethyl)-1H-pyrazol-1-yl)propan-1-ol:

[551] To a solution of LiAlH ₄ (1.2 g, 30.3 mmol) in THF (80 ml) was added ethyl 1-(3-hydroxypropyl)-1H-pyrazole-5-carboxylate (4.0 g, 20.2 mmol) at 0°C in a nitrogen atmosphere. After 1 hour, the reaction mixture was quenched with Na ₂ SO ₄ ⋅10H ₂ O. The reaction mixture was warmed to room temperature and left to stir for 10 minutes before removing solids by filtration. The filtrate was concentrated to give 3-(5-(hydroxymethyl)-1H-pyrazol-1-yl)propan-1-ol (3 g, yield: 95%) as a colorless oil, which was used in the next step without further purification. MS: m/z 156.8 (M+H ⁺ ).

Step 3 Synthesis of 4,6,7,8-tetrahydropyrazolo[5,1-e][1,4]oxazepine:

[552] A solution of 3-(5-(hydroxymethyl)-1H-pyrazol-1-yl)propan-1-ol (1.7 g, 10.9 mmol) in phosphoric acid (30 ml, 54.4 mmol) was stirred at 130°C for 20 hours. After cooling to room temperature, the reaction mixture was quenched with water (40 ml). The resulting mixture was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution and then extracted with DCM (30 ml x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated to give 4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine (400 mg , unrefined) as a colorless oil, which was used in the next step without further purification. MS: m/z 139.0 (M+H ⁺ ).

Step 4 Synthesis of 3-bromo-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine:

[553] To a solution of 4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine (650 mg, 4.7 mmol) in MeCN (10 ml) was added NBS (921 mg, 5. 2 mmol) at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was quenched with water (20 ml) and extracted with DCM (2×20 ml). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified using a silica gel column (0 50% EtOAc in petroleum ether) to give 3-bromo-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine (900 mg, yield: 88%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.33 (s, 1H), 4.66 (s, 2H), 4.46 (t, J=5.2 Hz, 2H), 4.05 ( t, J=5.2 Hz, 2H), 2.05-1.96 (m, 2H). MS: m/z 216.9 (M+H ⁺ ).

Step 5 Synthesis of N'-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfonimidamide:

[554] To a solution of 3-bromo-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine (200 mg, 0.9 mmol) in THF (5 ml), n was added dropwise -BuLi (2.5 M in hexane, 0.4 ml, 1.0 mmol) at -78°C under nitrogen. After stirring at -78°C for 0.5 hour, a solution of TrtNSO (310 mg, 1.0 mmol) in THF (2 ml) was added dropwise. The mixture was stirred at -78°C for 30 minutes before being placed in an ice bath. The reaction mixture was quenched with water (5 ml). The aqueous layer was extracted with DCM (2×10 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative TLC (silica, 5% methanol in DCM) to give N-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfinamide ( 180 mg, yield: 44%) as a white solid. MS: m/z 466.1 (M+Na ⁺ ).

[555] In a solution of N-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfinamide (180 mg, 0.4 mmol) in THF (4 ml) tert-butyl hypochlorite (49 mg, 0.4 mmol) was added dropwise at 0°C under nitrogen. After stirring at 0°C for 30 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified using a silica gel column (0 50% EtOAc in petroleum ether) to give N'-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3 -sulfonimidamide (160 mg, yield: 86%) as a white solid. MS: m/z 481.1 (M+Na ⁺ ).

Step 6 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-4,6,7,8-tetrahydropyrazolo[5, 1-c][1,4]oxazepine-3-sulfonimidamide:

[556] A solution of N'-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfonidamide (160 mg, 0.3 mmol) in THF (5 ml ) MeONa (23 mg, 0.4 mmol) was added at 0°C. After stirring for 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (84 mg, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (1 ml) and the mixture was concentrated. The crude residue was purified using a silica gel column (0-5% methanol in DCM) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'- trityl 4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfonidamide (160 mg, yield: 70%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ = 10.72 (s, 1H), 7.48-7.39 (m, 6H), 7.24-7.16 (m, 10H), 7.02 (s, 1H), 6.51 (s, 1H), 4.79 (d, J=15.2 Hz, 1H), 4.42-4.18 (m, 3H), 4.06-3, 81 (m, 2H), 2.91 (d, J=5.6 Hz, 8H), 2.14-2.07 (m, 4H), 2.00-1.90 (m, 2H).

Step 7 - (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-4,6,7,8-tetrahydropyrazolo [5,1-c][1,4]oxazepine-3-sulfonimidamide and (R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -N'-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfonimidamide:

[557] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-trityl-4,6,7,8-tetrahydropyrazolo[5,1- c][1,4]oxazepine-3-sulfonimidamide (160 mg, 0.2 mmol) was purified using chiral SLC (Chiralpak OD (250 mm * 30 mm, 10 μm), supercritical CO ₂ /MeOH + 0.1% NH ₄ OH = 55/45; 50 ml/min) to give (R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N' -Trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4]oxazepine-3-sulfonidamide (peak 1, 80 mg, yield: 50%) and (S)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-trityl-4,6,7,8-tetrahydropyrazolo[5,1-c][1,4] Oxazepine-3-sulfonimidamide (peak 2, 65 mg, yield: 40%), both as light yellow solids. Stereochemistry was randomly assigned to each stereoisomer. MS: m/z 680.1 (M+Na ⁺ ).

Step 8 - Synthesis of (S)-N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7,8-dihydro-4H,6H-pyrazolo[ 5,1-c][1,4]oxazepine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -7,8-dihydro-4H,6H-pyrazolo[5,1-e][1,4]oxazepine-3-sulfonidamide (Example 61 and Example 62):

[558] To a solution of material from peak 1 (80 mg, 0.1 mmol) in DCM (5 ml) was added MeSO ₃ H (59 mg, 0.6 mmol) at room temperature. After 20 minutes, the reaction mixture was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution and concentrated. The crude residue was purified by reverse phase chromatography (MeCN 35-65%/(0.04% NH ₄ OH + 0.1% NH ₄ HCO ₃ ) in water) to give (S)-N'-((l. ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7,8-dihydro-4H,6H-pyrazolo[5,1-c][1,4]oxazepine-3 -sulfonimidamide (method A, 1.55 min, 5.1 mg, 10% yield) as a white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.21 (s, 1H), 7.62 (s, 1H), 7.30 (s, 2H), 6.85 (s, 1H) , 4.99 (d, J=15.2 Hz, 1H), 4.81 (d, J=15.2 Hz, 1H), 4.46 (t, J=5.2 Hz, 2H), 4 .04-3.89 (m, 2H), 2.76 (t, J=7.2 Hz, 4H), 2.69-2.61 (m, 4H), 1.95-1.85 (m , 6H). MS: m/z 416.0 (M+H ⁺ ).

[559] The material from peak 2 above was deprotected and isolated in a similar manner to give (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -7,8-dihydro-4H,6H-pyrazolo[5,1-c][1,4]oxazepine-3-sulfonidamide (method A, 1.69 min, 14.4 mg, yield: 35%) as white solid. Stereochemistry was randomly assigned to each stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.21 (s, 1H), 7.62 (s, 1H), 7.30 (s, 2H), 6.85 (s, 1H) , 4.99 (d, J=15.2 Hz, 1H), 4.81 (d, J=15.2 Hz, 1H), 4.46 (t, J=5.2 Hz, 2H), 4 .04-3.89 (m, 2H), 2.76 (t, J=7.2 Hz, 4H), 2.69-2.61 (m, 4H), 1.95-1.85 (m , 6H). MS: m/z 416.1 (M+H ⁺ ).

Example 63

(R,6S)-N-cyano-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidine -1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia:

Step 1 - Synthesis of (R,6S)-N-cyano-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6- (3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide, ammonia (example 63):

[560] (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin- 1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (10 mg, 0.02 mmol) was dissolved in DMF (0.5 ml) and filled with triethylamine (1 M in DMF, 60 μl) and cyanogen bromide (1 M in CH ₂ Cl ₂ , 30 μl) at room temperature. After 30 minutes, 50 ml of saturated aqueous NaHCO ₃ solution was added. The mixture was directly purified by reverse phase HPLC (5%-50% ACN in 0.1% aqueous NH ₄ OH) to give the desired compound (4.5 mg, 45% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.38 (s, 1H), 7.07 (t, J=72 Hz, 3H), 4.40-4 .20 (m, 4H), 4.10-3.90 (m, 2H), 3.16 (s, 3H), 2.78 (t, J=7.2 Hz, 4H), 2.72 ( t, J=7.2 Hz, 4H), 2.05-1.95 (m, 4H). MS: m/z 530.2 (M+H ⁺ ).

Example 64, Example 65, Example 66 and Example 67

(S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7R)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide and (S,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo [5,1-b][1,3]oxazepine-3-sulfonimidamide:

Step 1 - Synthesis of 2-methylbutane-1,4-diol:

[561] A solution of 2-methylsuccinic acid (10 g, 75.7 mmol) in THF (200 ml) was added dropwise to a suspension of LiAlH ₄ (8.9 g, 234.6 mmol) in THF (200 ml) and the reaction was stirred mixture at 70°C for 24 hours. After cooling to room temperature, saturated aqueous Na ₂ SO ₄ solution was slowly added to quench the reaction. The mixture was filtered and the organic phase was concentrated to give the crude product, which was purified by silica gel chromatography (0-100% EtOAc in petroleum ether) to give 2-methylbutane-1,4-diol (6.5 g, yield: 82% ) in the form of a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=4.43 (t, J=5.2 Hz, 1H), 4.36 (t, J=5.2 Hz, 1H), 3.50- 3.38 (m, 2H), 3.29-3.22 (m, 1H), 3.21-3.13 (m, 1H), 1.63-1.47 (m, 2H), 1. 22-1.10 (m, 1H), 0.82 (d, J=6.8 Hz, 3H).

Step 2 - Synthesis of 2-methylbutane-1,4-diyl dimethanesulfonate:

[562] To a solution of 2-methylbutane-1,4-diol (6 g, 57.6 mmol) and triethylamine (40 mL, 288 mmol) in DCM (120 mL), MsCl (11.5 mL, 148 mmol) was added dropwise ) at 0°C. The reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was diluted with DCM (150 ml). The organic layer was washed with water (50 ml×2), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain 2-methylbutan-1,4-diyl dimethane sulfonate (14.6 g, yield: 97% ) in the form of a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=4.33-4.20 (m, 2H), 4.14-4.02 (m, 2H), 3.19 (s, 6H), 2.03-1.93 (m, 1H), 1.88-1.75 (m, 1H), 1.62-1.47 (m, 1H), 0.96 (d, J=6.8 Hz, 3H).

Step 3 - Synthesis of 7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine and 6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b ][1,3]oxazepine:

[563] To a stirred solution of 1H-pyrazol-5-ol (1.3 g, 15.6 mmol) in DMF (52 ml) was added K ₂ CO ₃ (7.5 g, 54.1 mmol). The mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. 2-Methylbutan-1,4-diyl dimethanesulfonate (4.8 g, 18.5 mmol) was then added and the mixture continued to stir at 100° C. for an additional 12 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (30% EtOAc in petroleum ether) to give 7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (300 mg , yield: 13%) and 6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (190 mg, yield: 8%), both as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.24 (d, J=2.0 Hz, 1H), 5.68 (d, J=2.0 Hz, 1H), 4.31-4 .22 (m, 2H), 3.91-3.81 (m, 2H), 2.04-1.96 (m, 2H), 1.90-1.79 (m, 1H), 1.04 (d, J=6.4 Hz, 3H). ^1H NMR (400 MHz, CDCl ₃ ): δ=7.24 (d, J=2.0 Hz, 1H), 5.68 (d, J=2.0 Hz, 1H), 4.37-4 .20 (m, 1H), 4.22-4.16 (m, 1H), 4.14-4.03 (m, 1H), 3.49-3.44 (m, 1H), 2.26 -2.12 (m, 1H), 2.01-1.93 (m, 1H), 1.57-1.43 (m, 1H), 0.99 (d, J=6.8 Hz, 3H ).

Step 4 - Synthesis of 3-bromo-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine:

[564] To a solution of 7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (1.2 g, 7.9 mmol) in MeCN (26 ml) was added NBS (1.4 g, 7.9 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed and the mixture was purified by flash chromatography (silica, 0-30% EtOAc in petroleum ether) to give 3-bromo-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b] [1,3]oxazepine (1.6 g, yield: 88%) as a white solid. MS: m/z 230.9 (M+H ⁺ ).

Step 5 - Synthesis of 7-methyl-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

[565] In a solution of 3-bromo-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (200 mg, 0.87 mmol) in THF (3 ml) n-BuLi (2.5 M in hexane, 0.4 ml, 0.95 mmol) was added dropwise at -78°C. The mixture was stirred at this temperature for 30 minutes. A solution of TrtNSO (291 mg, 0.95 mmol) in THF (1 ml) was added dropwise and the mixture was stirred at -78°C for 30 minutes before placing in an ice bath at 0°C. Tert-butyl hypochlorite (0.11 mL, 0.95 mmol) was then added and the mixture was stirred at 0° C. for 0.5 hour. NH ₃ gas was bubbled through the mixture for 10 minutes at 0° C. and the resulting solution was stirred for 16 hours at room temperature. The mixture was concentrated and the crude residue was purified by silica gel column chromatography (solvent gradient: 0-80% EtOAc in petroleum ether) to give 7-methyl-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1- b][1,3]oxazepine-3-sulfonimidamide (250 mg, yield: 61%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.48-7.41 (m, 6H), 7.21-7.17 (m, 6H), 7.14-7.08 (m , 3H), 7.04 (d, J=12.0 Hz, 1H), 6.20 (d, J=12.8 Hz, 2H), 4.32-4.18 (m, 1H), 4 .11-4.04 (m, 1H), 3.94-3.75 (m, 2H), 2.06-1.99 (m, 1H), 1.91-1.86 (m, 1H) , 1.84-1.69 (m, 1H), 0.94 (d, J=6.4 Hz, 3H).

Step 6 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-N'-trityl-5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

[566] In a stirred solution of 7-methyl-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (150 mg, 0.32 mmol) MeONa (34 mg, 0.63 mmol) was added to THF (5 ml) at 0°C. After 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (76 mg, 0.38 mmol) was added. The reaction mixture was warmed to room temperature and continued stirring for 16 hours. The reaction mixture was quenched with MeOH (1 ml). The mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-7-methyl-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (200 mg, yield: 94%) as a white solid substances.

Step 7 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5, 1-b][1,3]oxazepine-3-sulfonimidamide:

[567] Into a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-N'-trityl-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (200 mg, 0.30 mmol) in DCM (15 ml) was added MeSO ₃ H (10 drops) at room temperature. After 0.5 h, the reaction mixture was adjusted to pH=8 using a saturated aqueous solution of NaHCO ₃ . The reaction mixture was concentrated to dryness and the crude residue was purified by flash chromatography (silica, 0-1% MeOH in DCM) to give N'-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (100 mg, yield: 78%) as white solid. MS: m/z 430.1 (M+H ⁺ ).

Step 7 - (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (R,7R)-N'-((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine- 3-sulfonidamide and (S,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (Example 64, Example 65, Example 66 and Example 67):

[568] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide (160 mg, 0.37 mmol) was separated by SLC (Chiralpak ad (250 mm*50 mm, 10 μm)); supercritical CO ₂ /EtOH (0.1% NH ₄ OH) = 40/40, 80 ml/min)) to obtain peak 1 (method B, 3.04 min, 17 mg, yield: 11%), peak 2 ( method B, 3.45 min, 16.1 mg, yield: 10%) and 50 mg of a mixture of peak 3 and peak 4, which was separated using SLC (Cellulose-2 (250 mm * 30 mm, 10 μm); supercritical RM ₂ /EtOH (0.1% NH4OH) = 40/40, 70 ml/min) to obtain peak 3 (method B, 4.63 min, 22.3 mg, yield: 14%) and peak 4 (method B, 4.66 min, 23.8 mg, yield: 15%). Stereochemistry was randomly assigned to each stereoisomer.

[569] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ):: δ=8.23 (s, 1H), 7.50 (s, 1H), 7.30 (s, 2H), 6 .85 (s, 1H), 4.34-4.30 (m, 1H), 4.21-4.17 (m, 1H), 4.01-3.87 (m, 2H), 2.77 (t, J=7.2 Hz, 4H), 2.68-2.64 (m, 4H), 2.08-1.99 (m, 1H), 1.97-1.87 (m, 5H ), 1.85-1.75 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). MS: m/z 430.1 (M+H ⁺ ). Connection 64

[570] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.20 (s, 1H), 7.50 (s, 1H), 7.31 (s, 2H), 6, 85 (s, 1H), 4.32-4.27 (s, 1H), 4.20-4.17 (m, 1H), 4.05-3.87 (m, 2H), 2.77 ( t, J=7.2 Hz, 4H), 2.75-2.66 (m, 4H), 2.05-2.01 (m, 1H), 1.98-1.86 (m, 5H) , 1.86-1.73 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). Compound 66

[571] Peak 3: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.20 (s, 1H), 7.49 (s, 1H), 7.25 (s, 2H), 6, 85 (s, 1H), 4.32-4.27 (s, 1H), 4.20-4.17 (m, 1H), 3.97-3.87 (m, 2H), 2.77 ( t, J=7.2 Hz, 4H), 2.70-2.60 (m, 4H), 2.05-2.01 (m, 1H), 1.98-1.86 (m, 5H) , 1.86-1.73 (m, 1H), 0.94 (d, J=7.2 Hz, 3H). MS: m/z 430.1 (M+H ⁺ ). Connection 65

[572] Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.16 (s, 1H), 7.48 (s, 1H), 7.19 (s, 2H), 6, 84 (s, 1H), 4.31-4.27 (m, 1H), 4.19-4.16 (m, 1H), 4.02-3.88 (m, 2H), 2.76 ( t, J=7.2 Hz, 4H), 2.70-2.60 (m, 4H), 2.04-1.99 (m, 1H), 1.98-1.86 (m, 5H) , 1.85-1.72 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). MS: m/z 430.1 (M+H ⁺ ). Compound 67

Example 68

(R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonimidamide, ammonia:

[573] (R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonimidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-N'-((8-fluoro-1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 63), replacing (S,6S)-N'-((8-fluoro-l,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide on (S)-N '-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazine-3-sulfonimidamide in step 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.41 (s, 1H), 7.07 (t, J=72 Hz , 3H), 6.82 (s, 1H), 4.43-4.25 (m, 2H), 4.08 (t, J=6.1 Hz, 2H), 2.76 (t, J= 7.4 Hz, 4H), 2.72-2.60 (m, 4H), 2.17 (g, J=6.1 Hz, 2H), 1.92 (p, J=7.4 Hz, 4H). MS: m/z 427.2 (M+H ⁺ ).

Example 69

(S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonimidamide, ammonia

[574] (S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-N'-((8-fluoro-1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide (Example 63), replacing (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide on (R)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide in step 1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.72 (s, 1H), 7.36 (s, 1H), 6.79 (s, 1H), 6.51 (s, 1H), 4.42-4.21 (m, 2H), 4.07 (t, J=6.1 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H) , 2.70-2.60 (m, 4H), 2.20-2.10 (m, 2H), 2.00-1.79 (m, 4H). MS: m/z 427.2 (M+H ⁺ ).

Example 70 and Example 71

(S)-N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of 2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)-N-methylethanamine:

[575] To a mixture of NaH (60% in mineral oil, 660 mg, 16.48 mmol) in THF (20 ml) was added dropwise tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.59 g, 9. 06 mmol) in THF (10 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at 70°C for 0.5 hour. After cooling to room temperature, 6-chloro-2,4-diisopropyl-3-nitropyridine (2 g, 8.24 mmol) in THF (10 ml) was added dropwise. The resulting mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (50 ml×2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified using a silica gel column (0-10% MeOH in DCM) to give 2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)-N-methylethanamine (380 mg, yield: 17% ) in the form of a colorless oil. MS: m/z 282.1 (M+H ⁺ ).

Step 2 - Synthesis of tert-butyl (2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)ethyl)(methyl)carbamate:

[576] In a solution of 2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)-N-methylethanamine (380 mg, 1.35 mmol) and triethylamine (273 mg, 2.7 mmol) in DCM (5.4 ml) was added di-tert-butyl carbonate (354 mg, 1.62 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated. The crude residue was purified by TLC (silica, 20% EtOAc in petroleum ether) to give tert-butyl (2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)ethyl)(methyl)carbamate ( 385 mg, yield: 75%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=6.59 (s, 1H), 4.52 (t, J=5.2 Hz, 2H), 3.05 (t, J=5.2 Hz, 2H), 2.98-2.92 (m, 1H), 2.87-2.80 (m, 1H), 2.56 (s, 3H), 1.30-1.10 (m, 21H) .

Step 3 - Synthesis of tert-butyl (2-((5-amino-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate:

[577] In a solution of tert-butyl (2-((4,6-diisopropyl-5-nitropyridin-2-yl)oxy)ethyl)(methyl)carbamate (385 mg, 1.01 mmol) in EtOH (16 ml) 10% Pd (118 mg, 1.11 mmol) on carbon was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated to obtain tert-butyl (2-((5-amino-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (335 mg, yield: 94%) as a colorless liquid . ^1H NMR (400 MHz, CDCl ₃ ) δ=6.40 (s, 1H), 4.44-4.34 (m, 2H), 3.62-3.56 (m, 2H), 3.32 (s, 2H), 3.06-3.01 (m, 1H), 2.96 (s, 3H), 2.94-2.86 (m, 1H), 1.40 (s, 9H), 1.27-1.22 (m, 12H).

Step 4 - Synthesis of tert-butyl (2-((5-isocyanato-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate:

[578] In a solution of tert-butyl (2-((5-amino-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (260 mg, 0.74 mmol) and triethylamine (0.15 ml, 1.11 mmol) in anhydrous THF (3.7 ml) was added triphosgene (110 mg, 0.37 mmol) at room temperature. The mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give tert-butyl (2-((5-isocyanato-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (279 mg, yield: 99% ) as a white solid.

Step 5 - Synthesis of tert-butyl (2-((4,6-diisopropyl-5-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonimidoyl)ureido)pyridin-2-yl)oxy)ethyl)(methyl)carbamate:

[579] In a solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (219 mg, 0.49 mmol) in THF (13 ml ) MeONa (40 mg, 0.74 mmol) was added at 0°C under nitrogen. After stirring for 20 minutes, a solution of tert-butyl (2-((5-isocyanato-4,6-diisopropylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (279 mg, 0.74 mmol) in THF (8 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by preparative TLC (silica, 5% methanol in DCM) to give tert-butyl (2-((4,6-diisopropyl-5-(3-(N-trityl-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)ureido)pyridin-2-yl)oxy)ethyl)(methyl)carbamate (226 mg, yield: 56%) as white solid. MS: m/z 844.3 (M+Na ⁺ ).

Step 6 - Synthesis of N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide:

[580] Into a solution of tert-butyl (2-((4,6-diisopropyl-5-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazin-3-sulfonimidoyl)ureido)pyridin-2-yl)oxy)ethyl)(methyl)carbamate (226 mg, 0.27 mmol) in DCM (13 ml) was added with MeSO ₃ H (10 drops) at room temperature. After 1 hour, the reaction solution was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution. The reaction mixture was filtered and concentrated. The crude residue was purified by TLC (silica, 10% MeOH in DCM) to give N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (104 mg, yield: 79%) as a white solid. MS: m/z 480.1 (M+H ⁺ ).

Step 7 - (S)-N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazin-3-sulfonimidamide and (R)-N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 70 and Example 71):

[581] N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonidamide (104 mg, 0.22 mmol) was separated using chiral SLC (Chiralpak AD, (250 mm*30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH=65/35; 80 ml/min) to obtain (S)-N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (method S, 5.92 min, peak 1, 28.8 mg, yield: 27%) and (R)- N'-((2,4-diisopropyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide (Method S, 6.51 min, peak 2, 27.4 mg, yield: 26%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[582] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.97 (s, 1H), 7.47 (s, 1H), 6.43 (s, 1H), 4, 41-4.32 (m, 2H), 4.26 (t, J=5.6 Hz, 2H), 4.08 (m, J=6.0 Hz, 2H), 3.24-3.11 (m, 1H), 3.07-2.93 (m, 1H), 2.78 (t, J=5.6 Hz, 2H), 2.30 (s, 3H), 2.20-2, 12 (m, 2H), 1.12-1.00 (m, 12H). MS: m/z 480.2 (M+H ⁺ ).

[583] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.98 (s, 1H), 7.48 (s, 1H), 6.43 (s, 1H), 4, 42-4.33 (m, 2H), 4.26 (t, J=6.0 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.25-3.10 (m, 1H), 3.06-2.91 (m, 1H), 2.79 (t, J=5.6 Hz, 2H), 2.31 (s, 3H), 2.21-2, 14 (m, 2H), 1.12-1.00 (m, 12H). MS: m/z 480.2 (M+H ⁺ ).

Example 72 and Example 73

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrimidine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrimidine-3-sulfonimidamide:

Step 1 - Synthesis of tert-butyl 3-(N'-tritylsulfamidimidoyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate:

[584] A solution of tert-butyl 3-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidine-4-carboxylate (2.0 g, 6.62 mmol) in THF (32 ml) n-BuLi (2.5 M in hexane, 2.91 mL, 7.28 mmol) was added dropwise at -78°C under nitrogen. After stirring at -78°C for 0.5 hour, a solution of TrtNSO (2.22 g, 7.28 mmol) in THF (14 ml) was added dropwise. The mixture was stirred at -78°C for 20 minutes and then stirred at 0°C for 10 minutes. Tert-butyl hypochlorite (0.8 mL, 7.07 mmol) was then added dropwise at 0°C and the mixture was stirred at 0°C for 0.5 hour. NH ₃ gas was bubbled through the mixture for 10 minutes at 0° C. and the resulting mixture was stirred for 16 hours at room temperature. The mixture was concentrated and DCM/MeOH (20/1, 15 ml) was added. The resulting mixture was filtered and the solid was dissolved in water (20 ml), extracted with DCM/MeOH (9/1, 100 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 3-(N'-tritylsulfamidimidoyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (1 .9 g, yield: 54%) as a white solid. MS: m/z 566.1 (M+Na ⁺ ).

Step 2 - Synthesis of tert-butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydropyrazolo [1,5-a]pyrimidine-4(5H)-carboxylate:

[585] A solution of tert-butyl 3-(N'-tritylsulfamidimidoyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (120 mg, 0.22 mmol) in THF (5 ml) CH ₃ ONa (18 mg, 0.33 mmol) was added at 0°C under nitrogen atmosphere. After stirring at 0°C for 20 minutes, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (88 mg, 0.44 mmol) in THF (2 ml) was added. The reaction mixture was stirred at room temperature for 16 hours. MeOH (5 ml) was added and the mixture was filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0-1.5% methanol in DCM) to give tert-butyl 3-(N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-carboxylate (120 mg, yield: 73%) as a white solid. MS: m/z 743.4 (M+H ⁺ ).

Step 3 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrimidine-3-sulfonimidamide:

[586] In a solution of tert-butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7- Dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (120 mg, 0.16 mmol) in DCM (9 ml) was added with MeSO ₃ H (78 mg, 0.81 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (silica, 10% methanol in DCM) to give N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4, 5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonidamide (65 mg, yield: 91%) as a white solid. MS: m/z 401.2 (M+H ⁺ ).

Step 4 - (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrimidin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7 -tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonimidamide (Example 72 and Example 73)

[587] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine -3-sulfonimidamide (65 mg, 0.16 mmol) was separated using chiral SLC (Chiralpak AS (250 mm * 30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 75/25; 60 ml/min) to obtain (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidine-3-sulfonimidamide (method C, 3.65 min, peak 1, 29.1 mg, yield: 44%) and (R)-N'-((1,2,3, 5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonidamide (Method C, 4.47 min, peak 2, 31.4 mg, yield: 47%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[588] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.24 (s, 1H), 7.38 (s, 1H), 7.09 (s, 2H), 6. 88 (s, 1H), 6.43 (s, 1H), 3.96 (t, J=6.0 Hz, 2H), 3.29-3.10 (m, 2H), 2.79 (t , J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.04-1.86 (m, 6H). MS: m/z 401.2 (M+H ⁺ ).

[589] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (s, 1H), 7.37 (s, 1H), 7.09 (s, 2H), 6. 88 (s, 1H), 6.37 (s, 1H), 3.96 (t, J=6.0 Hz, 2H), 3.25-3.15 (m, 2H), 2.79 (t , J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.03-1.89 (m, 6H). MS: m/z 401.2 (M+H ⁺ ).

Example 74, Example 75, Example 78 and Example 79

(S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6S)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo [5,1-b][1,3]oxazepine-3-sulfonimidamide:

Steps 1-4 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonimidamide:

[590] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide was prepared using the general procedure described for the preparation of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-7-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (Example 64, Example 65, Example 66 and Example 67), replacing 7-methyl -5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine to 6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine at stage 4.

Step 5 - (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (R,6S)-N'-((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine- 3-sulfonidamide and (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide. (example 74, example 75, example 78 and example 79)

[591] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide (150 mg, 0.35 mmol) was separated using SLC (daicel chiralpak AD (250 mm * 30 mm, 10 μm); supercritical CO ₂ /MeOH (0.1 % NH ₃ H ₂ O) = 50/50 at 70 ml/min) to obtain peak 3 (method B, 5.32 min, 21.1 mg, yield: 14%), peak 4 (method B, 7.55 min, 22.5 mg, yield: 15%) and 50 mg of a mixture of peak 1 and peak 2, which were separated using SLC (regis (s,s) whelk-ol (250 mm * 30 mm, 5 μm); supercritical CO ₂ /IPA (0.1% NH ₃ H ₂ O) = 40/40 at 70 ml/min) to obtain peak 1 (method B, 3.32 min, 20.2 mg, yield: 13%) and peak 2 (Method B, 3.49 min, 18.7 mg, yield: 12%).

[592] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.22 (s, 1H), 7.49 (s, 1H), 7.28 (s, 2H), 6. 86 (s, 1H), 4.36-4.19 (m, 2H), 4.14-4.00 (m, 1H), 3.60-3.55 (m, 1H), 2.77 ( t, J=7.6 Hz, 4H), 2.70-2.66 (m, 4H), 2.23-2.13 (m, 1H), 1.97-1.90 (m, 5H) , 1.43-1.35 (m, 1H), 0.92 (d, J=6.8 Hz, 3H). m/z 430.1 (M+H ⁺ ). Connection 75

[593] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.51 (s, 1H), 7.31 (s, 2H), 6. 85 (s, 1H), 4.34-4.17 (m, 2H), 4.13-4.02 (m, 1H), 3.66-3.61 (m, 1H), 2.77 ( t, J=7.2 Hz, 4H), 2.68-2.66 (m, 4H), 2.20-2.13 (m, 1H), 1.96-1.89 (m, 5H) , 1.44-1.35 (m, 1H), 0.93 (d, J=6.8 Hz, 3H). m/z 430.1 (M+H ⁺ ). Connection 74

[594] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.51 (s, 1H), 7.31 (s, 2H), 6. 85 (s, 1H), 4.33-4.20 (m, 2H), 4.11-4.00 (m, 1H), 3.66-3.61 (m, 1H), 2.77 ( t, J=7.2 Hz, 4H), 2.70-2.66 (m, 4H), 2.21-2.13 (m, 1H), 1.98-1.89 (m, 5H) , 1.44-1.35 (m, 1H), 0.93 (d, J=6.8 Hz, 3H). MS: m/z 430.1 (M+H+). Connection 78

[595] Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.19 (s, 1H), 7.48 (s, 1H), 7.22 (s, 2H), 6, 85 (s, 1H), 4.34-4.20 (m, 2H), 4.13-4.02 (m, 1H), 3.60-3.55 (m, 1H), 2.77 ( t, J=7.2 Hz, 4H), 2.70-2.64 (m, 4H), 2.23-2.14 (m, 1H), 1.96-1.89 (m, 5H) , 1.45-1.34 (m, 1H), 0.93 (d, J=6.8 Hz, 3H). m/z 430.1 (M+H ⁺ ). Connection 79

Example 76 and Example 77

(R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazin-3-sulfonidamide and (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of 3-bromo-6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine:

To a solution of 6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine (1.27 g, 8.34 mmol) in MeCN (25 ml) NBS (1.49 g, 8.34 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give 3-bromo-6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine (1, 63 g, yield: 85%) as a light yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.33 (s, 1H), 3.96 (s, 2H), 3.84 (s, 2H), 1.15 (s, 6H).

Step 2 - Synthesis of 6,6-dimethyl-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

[596] In a solution of 3-bromo-6,6-dimethyl-5,7-dihydropyrazolo[5,1-b][1,3]oxazine (1.0 g, 4.33 mmol) in THF (15 ml) n-BuLi (2.5 M in hexane, 1.9 mL, 4.76 mmol) was added dropwise at -78°C under nitrogen. After 1 hour, a solution of TrtNSO (1.45 g, 4.76 mmol) in THF (15 ml) was added dropwise. The mixture was stirred at -78°C for 30 minutes before being placed in an ice bath at 0°C. Tert-butyl hypochlorite (0.54 mL, 4.76 mmol) was added. After 30 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes at 0°C. The resulting mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-100% EtOAc in petroleum ether) to give 6,6-dimethyl-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonidamide (960 mg, yield: 47%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.43 (d, J=7.6 Hz, 6H), 7.20-7.14 (m, 6H), 7.12-7, 06 (m, 3H), 6.98 (s, 1H), 6.25 (s, 2H), 3.98-3.87 (m, 2H), 3.74-3.63 (m, 2H) , 1.01 (s, 3H), 0.99 (s, 3H).

Step 3 - Synthesis of N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide:

[597] To a stirred mixture of 2,4-diisopropyl-6-methoxy-pyridin-3-amine (400 mg, 1.92 mmol) and triethylamine (0.4 ml, 2.88 mmol) in THF (8 ml) was added triphosgene (170 mg, 0.57 mmol). The reaction mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to give 3-isocyanato-2,4-diisopropyl-6-methoxy-pyridine (400 mg, yield: 89%) as a yellow oil.

[598] In a solution of 6,6-dimethyl-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (400 mg, 0.85 mmol ) in THF (16 ml) was added MeONa (69 mg, 1.27 mmol) at 0°C under nitrogen atmosphere. After 15 minutes, 3-isocyanato-2,4-diisopropyl-6-methoxy-pyridine (397 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by preparative TLC (silica, 50% ethyl acetate in petroleum ether) to give N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl- N'-Trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (430 mg, yield: 72%) as a white solid. ^1H NMR (400 MHz, MeOD): δ=7.46-7.37 (m, 6H), 7.25-7.19 (m, 9H), 6.86 (s, 1H), 6.52 (s, 1H), 4.00 (s, 2H), 3.91-3.85 (m, 3H), 3.73-3.62 (m, 2H), 3.42-3.34 (m , 1H), 3.20 (m, 1H), 1.30-1.18 (m, 1H), 1.30-1.18 (m, 10H), 1.12-1.03 (m, 7H ).

Step 4 - Synthesis of N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonimidamide:

[599] In a solution of N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (380 mg, 0.54 mmol) in THF (30 ml) was added MeSO ₃ H (0.17 ml, 2.69 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution and concentrated. The residue was purified by preparative TLC to give N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide (300 mg, crude, purity: 80%) as a white solid. MS: m/z 465.1 (M+H ⁺ ).

Step 5 - (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazin-3-sulfonidamide and (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 76 and example 77):

[600] N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]Oxazine-3-sulfonidamide (240 mg, 0.52 mmol) was separated using chiral SLC (Chiralpak IC (250 mm*30 mm, 5 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH=30 /70; 65 ml/min) to obtain (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (method D, 4.07 min, peak 1, 36.4 mg, yield: 15%) and (S)-N'-(( 2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide ( method D, 4.46 min, peak 2, 39.2 mg, yield: 16%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[601] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.98 (s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 6. 44 (s, 1H), 4.11-3.98 (m, 2H), 3.85 (s, 2H), 3.80 (s, 3H), 3.21-3.12 (m, 1H) , 3.05-2.94 (m, 1H), 1.15-0.96 (m, 18H). MS: m/z 465.1 (M+H ⁺ ). Connection 76

Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ=7.98 (s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 6.44 (s , 1H), 4.09-3.98 (m, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 3.20-3.13 (m, 1H), 3, 03-2.93 (m, 1H), 1.15-0.94 (m, 18H). MS: m/z 465.1 (M+H ⁺ ). Connection 77

Example 80 and Example 81

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[602] (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )Carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared by separating the racemic mixture of N'-(tert-butyldimethylsilyl)- N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonimidamide by chiral preparative HPLC (TBS deprotection occurs during the purification process) to obtain the two required isomers, peak 1 (Method U, 0.60 min) and peak 2 (Method U , 1.17 min), as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[603] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (br s, 1H), 7.54 (s, 1H), 7.24 (br s, 2H), 6.85 (s, 1H), 4.11-4.02 (m, 2H), 3.86 (s, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.68 (t, J=7.4 Hz, 4H), 1.99-1.86 (m, 4H), 1.04 (s, 3H), 1.03 (s, 3H). MS: m/z 430.2 (M+H ⁺ ).

[604] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (br s, 1H), 7.51 (s, 1H), 7.11 (br s, 2H), 6.84 (s, 1H), 4.08-4.02 (m, 2H), 3.85 (s, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.68 (t, J=7.4 Hz, 4H), 1.98-1.86 (m, 4H), 1.04 (s, 3H), 1.03 (s, 3H). MS: m/z 430.2 (M+H ⁺ ).

Example 82 and Example 83

(S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N'-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide:

Step 1 - Synthesis of tert-butyl ((6S)-3-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N' -tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate:

[605] Into a stirred solution of tert-butyl methyl((6S)-3-(N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl )carbamate (1.2 g, 2.09 mmol) in THF (30 ml) was added MeONa (226 mg, 4.18 mmol) in a 0°C ice bath. After 15 minutes, a solution of 4-fluoro-s-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.02 g, 4.70 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (5 ml) and concentrated. The crude residue was purified by silica gel column chromatography (0-9% methanol in dichloromethane) to give tert-butyl ((6S)-3-(N-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (610 mg, yield: 53%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.29-8.13 (m, 1H), 7.58-7.57 (m, 1H), 7.29-7.28 (m, 2H), 4.55-4.25 (m, 5H), 2.82-2.79 (m, 4H), 2.76-2.65 (m, 7H), 2.13-1.88 ( m, 4H), 1.42 (s, 9H). MS: m/z 571.1 (M+H ⁺ ).

Step 2 - Synthesis of (6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[606] Into a stirred solution of tert-butyl ((6S)-3-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- N'-tritylsulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (150 mg, 0.27 mmol) in DCM (6 .4 ml) MeSO ₃ H (0.06 ml, 0.94 mmol) was added at 0°C. After 30 minutes, NaHCO ₃ (solid) and H ₂ O (0.1 ml) were added until the reaction became basic. The mixture was concentrated and the crude residue was purified by preparative TLC (silica, 10% MeOH in DCM, 1% NH ₃ ⋅H ₂ O) to give (6S)-N'-((8-fluoro-1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonidamide (44 mg, yield: 36%) as a white solid.

[607] MS: m/z 449.0 (M+H ⁺ ).

Step 3 - (S,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-N'-((8-fluoro-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (example 82 and example 83):

[608] (6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7 -Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (110 mg, 0.25 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm) , supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 40/60; 60 ml/min) to obtain (S,6S)-N'-((8-fluoro-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method E, 2.16 min, peak 1, 37.8 mg, yield: 32%) and (R,6S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method E, 2.32 min, peak 2, 30.9 mg, yield: 26%), both as a white solid. Stereochemistry was randomly assigned to each stereoisomer.

[609] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.16 (s, 1H), 7.47 (s, 1H), 7.21 (s, 2H), 4.33 -4.30 (m, 1H), 4.24-4.16 (m, 2H), 3.91-3.87 (m, 1H), 3.20-3.13 (m, 1H), 2 .77 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 2.30 (s, 3H), 2.01-1.92 (m, 4H). MS: m/z 449.1 (M+H ⁺ ).

[610] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.20 (s, 1H), 7.50 (s, 1H), 7.24 (s, 2H), 4.36 -4.20 (m, 3H), 3.96-3.92 (m, 1H), 3.20-3.13 (m, 1H), 2.81 (t, J=7.2 Hz, 4H ), 2.74 (t, J=6.8 Hz, 4H), 2.34 (s, 3H), 2.04-1.97 (m, 4H), MS: m/z 449.1 (M +H ⁺ ).

Example 84 and Example 85

(S)-N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of tert-butyl ((4,6-diisopropyl-5-nitropyridin-2-yl)methyl)(methyl)carbamate:

[611] In a solution of 6-chloro-2,4-diisopropyl-3-nitropyridine (500 mg, 2.06 mmol), tert-butyl methyl ((4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)methyl)carbamate (726 mg, 2.68 mmol), K ₃ PO ₄ (1.3 g, 6.18 mmol) in 1,4-dioxane (5 ml) and water (0 .5 ml) CataCXium A Pd G2 (138 mg, 0.21 mmol) was added under nitrogen atmosphere. The mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml×2). The combined organic layers were washed with brine (50 ml×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give tert-butyl ((4,6-diisopropyl-5-nitropyridin-2-yl)methyl)(methyl)carbamate (440 mg, yield: 61%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) δ=7.08-7.00 (m, 1H), 4.55-4.45 (m, 2H), 3.07-2.94 (m, 4H) , 2.91-2.81 (m, 1H), 1.46-1.41 (m, 9H), 1.29-1.23 (m, 12H).

Step 2 Synthesis of tert-butyl ((5-amino-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate:

[612] To a solution of tert-butyl ((4,6-diisopropyl-5-nitropyridin-2-yl)methyl)(methyl)carbamate (440 mg, 1.25 mmol) in EtOH (10 ml) was added 10% palladium ( 133 mg, 0.13 mmol) on carbon. The mixture was stirred at room temperature under a hydrogen atmosphere (15 psi). After 2 hours, the mixture was filtered and the filtrate was concentrated to obtain tert-butyl ((5-amino-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate (300 mg, yield: 75%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ=6.88-6.80 (m, 1H), 4.45-4.34 (m, 2H), 3.60 (s, 2H), 3.07 -3.02 (m, 1H), 2.96-2.83 (m, 4H), 1.57-1.46 (m, 9H), 1.29-1.20 (m, 12H).

Step 3 - Synthesis of tert-butyl ((5-isocyanato-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate:

[613] In a solution of tert-butyl ((5-amino-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate (300 mg, 0.93 mmol) and triethylamine (0.26 ml, 1.87 mmol) in THF (6 ml) was added triphosgene (70 mg, 0.24 mmol) at 0°C. The reaction mixture was stirred at 50°C for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give tert-butyl ((5-isocyanato-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate (300 mg, yield: 93%) as a yellow oil .

Step 4 - Synthesis of tert-butyl ((4,6-diisopropyl-5-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonimidoyl)ureido)pyridin-2-yl)methyl)(methyl)carbamate:

[614] To a stirred solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (300 mg, 0.67 mmol) in THF (12 ml) MeONa (73 mg, 1.35 mmol) was added at 0°C under nitrogen atmosphere. After 15 minutes, tert-butyl ((5-isocyanato-4,6-diisopropylpyridin-2-yl)methyl)(methyl)carbamate (281 mg, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (1 ml) and the resulting mixture was concentrated. The residue was purified by silica gel column chromatography (0-5% methanol in DCM) to give tert-butyl ((4,6-diisopropyl-5-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-sulfonimidoyl)ureido)pyridin-2-yl)methyl)(methyl)carbamate (260 mg, yield: 49%) as a light yellow solid. MS: m/z 792.3 (M+H ⁺ ).

Step 5 - Synthesis of N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonimidamide:

[615] Into a solution of tert-butyl ((4,6-diisopropyl-5-(3-(N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidoyl)ureido)pyridin-2-yl)methyl)(methyl)carbamate (200 mg, 0.25 mmol) in DCM (12 ml) was added MeSO ₃ H (121 mg, 1.26 mmol) at room temperature. After 2 hours, the reaction mixture was adjusted to pH=8 with saturated aqueous NaHCO ₃ solution and concentrated. The crude residue was purified by preparative TLC (silica, 10% methanol in DCM) to give N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (90 mg, yield: 79%) as a light yellow solid. MS: m/z 450.2 (M+H ⁺ ).

Step 6 - (S)-N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (example 84 and example 85):

[616] N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonidamide (105 mg, 0.23 mmol) was purified using chiral SLC (Chiralpak IC (250 mm*30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH=50 /50; 70 ml/min), to obtain (S)-N'-((2,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (method F, 5.43 min, peak 1, 19 mg, yield: 17%) and (R)-N'-((2 ,4-diisopropyl-6-((methylamino)methyl)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method F, 7.26 min, peak 2, 17.3 mg, yield: 15%), both as light yellow solids. Stereochemistry was randomly assigned to each stereoisomer.

[617] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.10 (s, 1H), 7.46 (s, 1H), 7.06 (s, 1H), 4. 37-4.25 (m, 2H), 4.10-4.01 (m, 2H), 3.63 (s, 2H), 3.22-3.15 (m, 1H), 3.08- 2.99 (m, 1H), 2.29 (s, 3H), 2.20-2.10 (m, 2H), 1.10-1.00 (m, 12H). MS: m/z 450.3 (M+H ⁺ ).

[618] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.11 (s, 1H), 7.49 (s, 1H), 7.09 (s, 1H), 4. 46-4.30 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.63 (s, 2H), 3.25-3.15 (m, 1H), 3 .13-3.01 (m, 1H), 2.30 (s, 3H), 2.20-2.10 (m, 2H), 1.12-1.00 (m, 12H). MS: m/z 450.3 (M+H ⁺ ).

Example 88, Example 89, Example 90 and Example 91

(S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (S,7R)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide and (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo [5,1-b][1,3]oxazepine-3-sulfonimidamide:

Step 1 - Synthesis of diethyl 2-(benzyloxy)succinate:

[619] To a mixture of diethyl malate (35 g, 184 mmol) and Ag ₂ O (85.3 g, 368.1 mmol) in EtOAc (460 ml), BnBr (31.5 g, 184.0 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 12 hours in the dark. The reaction mixture was filtered through a small pad of celite. The filtrate was concentrated to give diethyl 2-(benzyloxy)succinate (50 g, yield: 97%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ=7.39-7.28 (m, 5H), 4.83-4.49 (m, 2H), 4.41-4.38 (m, 1H) , 4.29-4.09 (m, 4H), 2.88-2.71 (m, 2H), 1.33-1.22 (m, 6H).

Step 2 - Synthesis of 2-benzyloxybutane-1,4-diol:

[620] To a mixture of LiAlH ₄ (10.2 g, 267.6 mmol) in THF (381 ml) was added a solution of diethyl 2-(benzyloxy)succinate (30 g, 107.0 mmol) in THF (96 ml) at 0 °C in a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 12 hours. The mixture was cooled to 0°C and then quenched with water (12 ml), 15% aqueous NaOH (12 ml) and finally additional water (36 ml). The mixture was filtered and concentrated to give 2-benzyloxybutane-1,4-diol (15 g, yield: 71%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.40-7.28 (m, 5H), 4.61 (d, J=2.0 Hz, 2H), 3.81-3.68 (m , 4H), 3.65-3.58 (m, 1H), 2.63 (s, 2H), 1.94-1.77 (m, 2H).

Step 3 - Synthesis of 2-(benzyloxy)butane-1,4-diyl dimethanesulfonate:

[621] To a solution of 2-benzyloxybutane-1,4-diol (10 g, 50.9 mmol) and triethylamine (24 mL, 173.1 mmol) in DCM (108 mL), MsCl (9.6 mL, 124.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (80 ml). The aqueous layer was extracted with DCM (50 ml×2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 2-(benzyloxy)butane-1,4-diyl dimethanesulfonate (17.5 g, yield: 97%) as a brown oil. ^1H NMR (400 MHz, CDCl ₃ ) δ=7.41-7.29 (m, 5H), 4.75-4.54 (m, 2H), 4.44-4.31 (m, 3H) , 4.24-4.20 (m, 1H), 3.92-3.85 (m, 1H), 3.02 (s, 3H), 2.96 (s, 3H), 2.10-1 .97 (m, 2H).

Step 4 - Synthesis of 7-benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine and 6-benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b ][1,3]oxazepine:

[622] To a stirred solution of 1H-pyrazol-5-ol (55 g, 65.4 mmol) in DMF (200 ml) was added K ₂ CO ₃ (31.6 g, 229 mmol) and the mixture was stirred at 130°C in within 30 minutes. A solution of 2-(benzyloxy)butane-1,4-diyl dimethanesulfonate (27.7 g, 78.5 mmol) in DMF (50 ml) was then added and the mixture was left to stir at 130° C. for a further 16 hours. After cooling to room temperature, the mixture was filtered and concentrated. The crude residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give 7-benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (5.7 g, yield: 36%) and 6-benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (720 mg, yield: 5%), both as a colorless oil.

[623] 7-Benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine: ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.37-7.29 ( m, 6H), 5.71 (d, J=2.0 Hz, 1H), 4.72 (d, J=12 Hz, 1H), 4.55-4.52 (m, 2H), 4, 29-4.19 (m, 2H), 4.13-4.05 (m, 1H), 3.82-3.78 (m, 1H), 2.23-2.18 (m, 2H).

[624] 6-Benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine: ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.41-7.29 ( m, 5H), 7.24 (d, J=2.0 Hz, 1H), 5.71 (d, J=2.0 Hz, 1H), 4.68 (s, 2H), 4.53- 4.44 (m, 1H), 4.16-4.07 (m, 2H), 4.07-4.02 (m, 1H), 3.86-3.80 (m, 1H), 2. 11-2.04 (m, 2H).

Step 5 - Synthesis of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol:

[625] To a stirred solution of 7-benzyloxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (3 g, 12.3 mmol) in EtOH (30 ml) was added 10% wet palladium (1.5 g, 1.4 mmol) on carbon and stirred the mixture at 50° C. under H ₂ (45 psi). After 12 hours, the reaction mixture was cooled to room temperature and filtered through a small pad of celite. The filtrate was concentrated and the crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol (1 .4 g, yield: 75%) as a white solid. MS: m/z 154.8 (M+H ⁺ ).

Step 6 - Synthesis of 7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine:

[626] To a solution of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol (1.5 g, 9.7 mmol) in MeCN (30 ml) was added MeI (1.8 ml, 28.9 mmol) and Ag ₂ O (4.5 g, 19.5 mmol) at room temperature. After 16 hours, the reaction mixture was filtered through a small pad of celite. The celite layer was washed with EtOH (2 ml×3). The filtrate was concentrated and the crude residue was purified by silica gel column chromatography (40% EtOAc in petroleum ether) to give 7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (1 .25 g, yield: 76%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.30-7.26 (m, 1H), 5.69 (d, J=2.0 Hz, 1H), 4.50-4.45 (m , 1H), 4.25-4.07 (m, 3H), 3.64-3.58 (m, 1H), 3.41 (s, 3H), 2.22-2.16 (m, 2H ).

Step 7 - Synthesis of 3-bromo-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine:

[627] To a solution of 7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (1.13 g, 6.7 mmol) in MeCN (24 ml) was added NBS (1.2 g, 6.7 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography (silica, 30% EtOAc in petroleum ether) to give 3-bromo-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b ][1,3]oxazepine (1.38 g, yield: 83%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.28 (s, 1H), 4.53-4.48 (m, 1H), 4.24-4.17 (m, 3H), 3.65 -3.61 (m, 1H), 3.39 (s, 3H), 2.24-2.20 (m, 2H).

Step 8 - Synthesis of 7-methoxy-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

[628] In a solution of 3-bromo-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (600 mg, 2.4 mmol) in THF (20 ml) n-BuLi (2.5 M in hexane, 1.2 ml, 3.0 mmol) was added dropwise at -78°C. After 1 hour, a solution of TrtNSO (890 mg, 2.9 mmol) in THF (2 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 20 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. t-BuOCl (0.3 mL, 2.9 mmol) was added dropwise at 0°C. After 20 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give 7-methoxy-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1 ,3]oxazepine-3-sulfonidamide (200 mg, 33% yield) as a white solid. MS: m/z 511.1 (M+H ⁺ ).

Step 9 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-N'-trityl-5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

[629] In a stirred solution of 7-methoxy-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (657 mg, 1.3 mmol) MeONa (109 mg, 2.0 mmol) was added to THF (10 ml) at 0°C under a nitrogen atmosphere. After 20 minutes, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (536 mg, 2.7 mmol) in THF (2 ml) was added. The reaction mixture was left stirring at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude residue was purified by column chromatography (silica, 50% EtOAc in petroleum ether) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7 -methoxy-N'-trityl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (605 mg, yield: 65%) as a white solid. MS: m/z 710.1 (M+H ⁺ ).

Step 10 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5, 1-b][1,3]oxazepine-3-sulfonimide amide:

[630] Into a stirred solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-N'-trityl-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (605 mg, 0.9 mmol) in DCM (46 ml) was added MeSO ₃ H (0.06 ml, 0.9 mmol) at room temperature. After 1 hour, water (1 ml) was added and the reaction mixture was made alkaline with NaHCO ₃ (solid) to pH=8. The mixture was filtered and washed with MeOH (20 ml). The filtrate was concentrated and the crude residue was purified by preparative TLC (silica, 5% MeOH in DCM) to give N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (191 mg, yield: 49%) as a white solid. MS: m/z 446.0 (M+H ⁺ ).

Step 11 - (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (S,7R)-N'-((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine- 3-sulfonidamide and (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (Example 88, Example 89, Example 90 and Example 91):

[631] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide (212 mg, 0.48 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm, supercritical CO ₂ /MeOH + 0.1% NH ₄ OH=60/40; 80 ml/min), obtaining peak 3 (method G, 4.71 min, 331.5 mg, yield: 15%), peak 4 ((method G, 7.64 min, 34.8 mg, yield: 16%) and 84 mg of a mixture of peak 1 and peak 2, which was separated using chiral SLC (Cellulose-2 (250 mm * 30 mm, 10 μm, supercritical CO ₂ /MeOH + 0.1% NH ₄ OH=45/55; 80 ml/min) to obtain peak 1 (method H, 3.68 min, 35 mg, yield: 17%) and peak 2 (method H, 4.78 min, 30.4 mg , yield: 14%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[632] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.19 (s, 1H), 7.52 (s, 1H), 7.33 (s, 2H), 6.86 (s, 1H), 4.52-4.48 (m, 1H), 4.28-4.20 (m, 2H), 4.12-4.05 (m, 1H), 3.70-3 .67 (m, 1H), 3.26 (s, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 2 .20-2.12 (m, 2H), 1.96-1.89 (m, 4H). MS: m/z 446.1 (M+H ⁺ ). Connection 90

[633] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.23 (s, 1H), 7.50 (s, 1H), 7.31 (s, 2H), 6.86 (s, 1H), 4.52-4.48 (m, 1H), 4.28-4.21 (m, 2H), 4.07-4.02 (m, 1H), 3.69-3 .66 (m, 1H), 3.26 (s, 3H), 2.78 (t, J=7.2 Hz, 4H), 2.69-2.62 (m, 4H), 2.19- 2.13 (m, 2H), 1.97-1.89 (m, 4H). MS: m/z 446.1 (M+H ⁺ ). Connection 91

[634] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.22 (s, 1H), 7.50 (s, 1H), 7.30 (s, 2H), 6.86 (s, 1H), 4.52-4.47 (m, 1H), 4.28-4.20 (m, 2H), 4.07-4.02 (m, 1H), 3.70-3 .66 (m, 1H), 3.26 (s, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.70-2.60 (m, 4H), 2.20- 2.11 (m, 2H), 1.96-1.89 (m, 4H), MS: m/z 446.1 (M+H ⁺ ). Connection 88

[635] Peak 4: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.18 (s, 1H), 7.52 (s, 1H), 7.32 (s, 2H), 6.86 (s, 1H), 4.53-4.48 (m, 1H), 4.27-4.20 (m, 2H), 4.11-4.06 (m, 1H), 3.70-3 .66 (m, 1H), 3.26 (s, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.67-2.61 (m, 4H), 2.20- 2.12 (m, 2H), 1.96-1.91 (m, 4H), MS: m/z 446.1 (M+H ⁺ ). Connection 89

Example 86, Example 87, Example 92 and Example 93

(S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (S,6S)-N'-((1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide and (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo [5,1-b][1,3]oxazepine-3-sulfonimidamide:

Step 1~6 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonimidamide:

[636] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide was prepared using the general procedure described for the preparation of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (Example 86, Example 87, Example 92 and Example 93), replacing 7-( benzyloxy)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine on 6-(benzyloxy)-5,6,7,8-tetrahydropyrazolo[5,1-b][1 ,3]oxazepine at stage 5.

Step 7 - (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8 -tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (S,6S)-N'-((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine- 3-sulfonidamide and (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (Example 86, Example 87, Example 92 and Example 93):

[637] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]oxazepine-3-sulfonimidamide (103 mg, 0.23 mmol) was separated using chiral SLC (Chiralpak AD (250 mm*30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1 % NH ₄ OH=50/50; 70 ml/min), obtaining peak 1 (method I, 2.95 min, 14.9 mg, yield: 14%), peak 2 (method I, 3.69 min, 14 mg, yield: 13%), peak 3 (method I, 4.59 min, 15.9 mg, yield: 14%) and peak 4 (method I, 8.46 min, 18 mg, yield: 17%) , all as a white solid. Stereochemistry was randomly assigned to each stereoisomer.

[638] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.22 (s, 1H), 7.50 (s, 1H), 7.29 (s, 2H), 6.85 (s, 1H), 4.27-4.22 (m, 2H), 4.12-4.04 (m, 2H), 3.73-3.67 (m, 1H), 3.32 (s , 3H), 2.76 (t, J=6.8 Hz, 4H), 2.71-2.66 (m, 4H), 1.96-1.90 (m, 6H). MS: m/z 446.1 (M+H ⁺ ). Connection 86

[639] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.14 (s, 1H), 7.47 (s, 1H), 7.27 (s, 2H), 6.82 (s, 1H), 4.23-4.18 (m, 2H), 4.07-4.04 (m, 2H), 3.67-3.66 (m, 1H), 3.32 (s , 3H), 2.73 (t, J=7.2 Hz, 4H), 2.62-2.52 (m, 4H), 1.92-1.84 (m, 6H). MS: m/z 446.1 (M+H ⁺ ). Connection 87

[640] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.13 (s, 1H), 7.46 (s, 1H), 7.22 (s, 2H), 6.81 (s, 1H), 4.24-4.18 (m, 2H), 4.15-4.05 (m, 2H), 3.69-3.66 (m, 1H), 3.32 (s , 3H), 2.73 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.92-1.80 (m, 6H). MS: m/z 446.1 (M+H ⁺ ). Connection 92

Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ) δ=8.19 (s, 1H), 7.50 (s, 1H), 7.25 (s, 1H), 6.85 (s, 1H), 4.27-4.21 (m, 2H), 4.13-4.02 (m, 4H), 3.72-3.68 (m, 1H), 3.35 (s, 3H) , 2.76 (t, J=7.2 Hz, 4H), 2.69-2.60 (m, 4H), 1.96-1.88 (m, 6H). MS: m/z 446.1 (M+H ⁺ ). Connection 93

Example 94

N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide

[641] (N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-6-(dimethylamino)-N'-(( 8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (N'-((1,2,3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide in step 1 (mixture of enantiomers) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (s, 1H), 7.38 (s, 1H), 6.79 (s, 1H), 4.05-3 .94 (m, 2H), 3.82 (s, 2H), 2.79-2.61 (m, 8H), 1.90 (p, J=7.3 Hz, 4H), 1.03 ( s, 3H), 1.02 (s, 3H). MS: m/z 455.2 (M+H ⁺ ).

Example 95

(S)-N-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonimidoyl)acetamide:

Step 1 - Synthesis of (S)-N-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl)acetamide (example 95):

[642] Acetyl chloride (2.1 mg, 1.9 µl, 26 µmol) was added dropwise to a solution of (R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (10 mg, 24 µmol) in pyridine (1.0 ml) at 0°C. After 1 hour, toluene (10 ml) was added and the mixture was concentrated under reduced pressure. The crude residue was dissolved in MeOH (1 ml) and purified by preparative HPLC to give (S)-N-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-ind acene -4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide (2.0 mg, yield: 18% as unknown stereoisomer ) as a white solid. MS: m/z 462 (M+H ⁺ ).

Example 96 and Example 97

(R)-N'-((1-(2,2-difluoroethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonimidamide and (S)-N'-((1-(2,2-difluoroethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

[643] (R)-N'-((1-(2,2-difluoroethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-sulfonimidamide and (S)-N'-((1-(2,2-difluoroethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide was prepared using the general procedure described for the preparation of (S)-N'-((1-ethyl- 3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N' -((1-ethyl-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 98 and Example 99), replacing iodoethane with 1,1-difluoro-2-iodoethane in step 3. After preparative HPLC and chiral preparative (Step 6), two isomers with unknown absolute stereochemistry were isolated, peak 1 (method T, 0 .49 min) and peak 2 (T method, 0.78 min).

[644] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (s, 1H), 7.48 (s, 1H), 7.21 (s, 2H), 6.52- 5.98 (m, 1H), 4.56-4.21 (m, 4H), 4.09 (t, J=6.1 Hz, 2H), 2.96 (k, J=7.0 Hz , 1H), 2.79-2.65 (m, 1H), 2.17 (k, J=4.8 Hz, 2H), 1.27-0.96 (m, 12H). MS: m/z 460.2 (M+H ⁺ ).

[645] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (s, 1H), 7.48 (s, 1H), 7.24 (d, J=19.3 Hz, 2H), 6.46-6.03 (m, 1H), 4.56-4.21 (m, 4H), 4.09 (t, J=6.1 Hz, 2H), 2.97 (p , J=7.0 Hz, 1H), 2.73 (p, J=6.9 Hz, 1H), 2.25-2.07 (m, 2H), 1.32-0.88 (m, 12H). MS: m/z 460.2 (M+H ⁺ ).

Example 98 and Example 99

(S)-N'-((1-ethyl-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-3-sulfonidamide and (R)-N'-((1-ethyl-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonimidamide:

Step 1: Synthesis of 3,5-diisopropyl-1H-pyrazole:

[646] Hydrazine (330 mg, 10 mmol) was added to a solution of 2,6-dimethylheptane-3,5-dione (1.6 g, 10 mmol) in ethanol (40 ml) at room temperature. After 2 hours, the reaction mixture was concentrated in vacuo to give 3,5-diisopropyl-1H-pyrazole (1.5 g, 10 mmol, yield: 100%) which was used in the next step without further purification. MS: m/z 153.1 (M+H ⁺ ).

Step 2: Synthesis of 3,5-diisopropyl-4-nitro-1H-pyrazole:

[647] 3,5-Diisopropyl-1H-pyrazole (1.5 g, 10.0 mmol) was dissolved in concentrated nitric acid (3.2 ml) and concentrated sulfuric acid (2.4 ml), and the solution was heated at 100 °C. After 10 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 3,5-diisopropyl-4-nitro-1H-pyrazole (1.6 g, 8.4 mmol, yield: 84%) which was used in the next step without additional purification. MS: m/z 198.1 (M+H ⁺ ).

Step 3: Synthesis of 1-ethyl-3,5-diisopropyl-4-nitro-1H-pyrazole:

[648] Iodoethane (1.1 g, 6.8 mmol) was added to a mixture of 3,5-diisopropyl-4-nitro-1H-pyrazole (1.2 g, 6.2 mmol) and K ₂ CO ₃ (940 mg , 6.8 mmol) in DMF (30 ml) and heated the reaction mixture at 50°C. After 4 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (3×), dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-ethyl-3,5-diisopropyl-4-nitro-1H-pyrazole (1.5 g, 6.0 mmol, yield : 96%), which was used in the next step without further purification. MS: m/z 226.1 (M+H ⁺ ).

Step 4: Synthesis of 1-ethyl-3,5-diisopropyl-1H-pyrazol-4-amine:

[649] Concentrated HCl (1.5 ml) was added to a mixture of 1-ethyl-3,5-diisopropyl-4-nitro-1H-pyrazole (1.5 g, 6.0 mmol) and zinc (1.2 g, 18.0 mmol) in acetic acid (80 ml) at room temperature. After 15 minutes, the reaction mixture was diluted with ethyl acetate. The organic matter was washed with saturated aqueous sodium bicarbonate and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica, 1-10% MeOH in DCM) to give 1-ethyl-3,5-diisopropyl-1H-pyrazol-4-amine (1.1 g, 5.0 mmol , yield: 83%). MS: m/z 1961.2 (M+H ⁺ ).

Step 5: Synthesis of 1-ethyl-4-isocyanato-3,5-diisopropyl-1H-pyrazole:

[650] Triphosgene (177 mg, 0.6 mmol) was added to a solution of 1-ethyl-3,5-diisopropyl-1H-pyrazol-4-amine (361 mg, 1.7 mmol) and triethylamine (201 mg, 2. 0 mmol) in THF (8 ml) and heated the mixture at 80°C. After 1 hour, the reaction mixture was filtered and concentrated in vacuo to give 1-ethyl-4-isocyanato-3,5-diisopropyl-1H-pyrazole (375 mg, 1.7 mmol, 100% yield), which was used directly in the next step without additional cleaning. MS: m/z 222.1 (M+H ⁺ ).

Step 6: Synthesis of (S)-N'-((1-ethyl-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-3-sulfonidamide and (R)-N'-((1-ethyl-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide (Example 98 and Example 99):

[651] NaH (60% in mineral oil, 46 mg, 1.8 mmol) was added to a solution of N'-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonidamide (397 mg, 0.9 mmol) and 1-ethyl-4-isocyanato-3,5-diisopropyl-1H-pyrazole (200 mg, 0.9 mmol) in THF (3 ml) at room temperature. After 10 minutes, the reaction mixture was cooled to 0°C. Water (0.5 ml) was added and the reaction mixture was concentrated in vacuo. HCl (4 M in dioxane, 2 ml) was added to the crude residue and the reaction mixture was allowed to stir at room temperature for 30 minutes. The mixture was concentrated in vacuo. The crude residue was co-evaporated with dioxane (2x), then purified by reverse phase HPLC (0.1% NH ₄ OH:ACN) and chiral SLC (Chiralcel OX (150 × 21 mm, 5 µm), methanol w/0 .1% NH ₄ OH) to obtain peak 1 ((method V, 0.45 min, 20 mg, yield: 5.2%) and peak 2 (method V, 0.67 min, 20 mg, yield: 5, 2%). Stereochemistry was randomly assigned to each stereoisomer.

[652] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (s, 1H), 7.48 (s, 1H), 7.21 (s, 2H), 4.44- 4.29 (m, 2H), 4.09 (t, J=6.1 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 2.93 (p, J=7 .0 Hz, 2H), 2.73 (g, J=7.1 Hz, 2H), 2.17 (k, J=4.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.17 (d, J=7.0 Hz, 6H), 1.09 (dd, J=6.9, 2.1 Hz, 6H). MS: m/z 424.2 (M+H ⁺ ).

[653] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (s, 1H), 7.47 (s, 1H), 7.21 (s, 2H), 4.44- 4.29 (m, 2H), 4.09 (t, J=6.1 Hz, 2H), 3.93 (k, J=7.1 Hz, 2H), 2.92 (g, J=7 ,1 Hz, 1H), 2.73 (g, J=7.1 Hz, 1H), 2.17 (k, J=4.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.17 (d, J=7.1 Hz, 5H), 1.08 (dd, J=7.0, 2.1 Hz, 6H). MS: m/z 424.2 (M+H ⁺ ).

Example 100 and Example 101

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]thiazin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonimidamide:

Step 1 - Synthesis of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine:

[654] To a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine (190 mg, 1.36 mmol) in MeCN (6 ml) was added NBS (241 mg, 1. 36 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness and the crude residue was purified by silica gel column chromatography (0-9% EtOAc in PE) to give 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] thiazine (260 mg, yield: 87%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.45 (s, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.12 (t, J=5.6 Hz , 2H), 2.45-2.35 (m, 2H). MS: m/z 219.0 (M+H ⁺ ).

Step 2 - Synthesis of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonimidamide:

[655] To a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine (260 mg, 1.19 mmol) in THF (5 ml) n was added dropwise -BuLi (2.5 M in hexane, 0.5 ml, 1.31 mmol) at -78°C under N ₂ atmosphere. After 30 minutes, a solution of TrtNSO (400 mg, 1.31 mmol) in THF (1 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 30 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.15 mL, 1.31 mmol) was added dropwise at 0°C. After 30 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated to dryness and the crude residue was purified by silica gel column chromatography (0:80% EtOAc in PE) to give N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]thiazine-3-sulfonidamide (300 mg, yield: 54%) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.47-7.40 (m, 7H), 7.20-7.11 (m, 6H), 7.10-7.05 (m, 3H ), 6.32 (s, 2H), 4.11-3.95 (m, 2H), 2.99 (t, J=5.6 Hz, 2H), 2.24-2.11 (m, 2H).

Step 3 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]thiazine-3-sulfonidamide:

[656] Into a stirred solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide (200 mg, 0.43 mmol) in THF (6 ml) MeONa (26 mg, 0.48 mmol) was added at 0°C. After 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (104 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (1 mL), concentrated to dryness, and the crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give N-((1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide (220 mg, yield: 77 %) as a white solid.

Step 4 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]thiazine-3-sulfonimidamide:

[657] Into a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]thiazine-3-sulfonidamide (220 mg, 0.33 mmol) in DCM (12 ml) was added MeSO ₃ H (6 drops) at 0°C. The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was basified with saturated aqueous NaHCO ₃ solution, concentrated to dryness, and the crude residue was purified by silica gel column chromatography (0-1% MeOH in DCM) to give N'-((1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide (80 mg, yield: 40% ) as a white solid. MS: m/z 418.2 (M+H ⁺ ).

Step 5 - Synthesis of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]thiazin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide (Example 100 and Example 101):

[658] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]thiazine-3-sulfonimidamide (80 mg, 0.19 mmol) was separated using chiral SLC (Chiralpak AS (250 mm * 30 mm, 10 μm); supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 65/35; 70 ml/min) to give (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide (peak 1, 25 mg, 70% purity) as a white solid and (R)-N'-((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide ( method C, 4.21 min, peak 2, 17.2 mg, yield: 22%). Peak 1 was further purified using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm); supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 40/40; 80 ml/min) to obtain (S) -N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]thiazine-3-sulfonidamide (Method C, 3.97 min, peak 1, 14.4 mg, yield: 18%) as a white solid. Stereochemistry was randomly assigned to each stereoisomer.

[659] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.17 (s, 1H), 7.70 (s, 1H), 7.33 (s, 2H), 6, 85 (s, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.12 (t, J=5.2 Hz, 2H), 2.77 (t, J =7.2 Hz, 4H), 2.70-2.65 (m, 4H), 2.28-2.21 (m, 2H), 1.96-1.85 (m, 4H). MS: m/z 418.0 (M+H ⁺ ).

[660] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.18 (s, 1H), 7.71 (s, 1H), 7.36 (s, 2H), 6. 86 (s, 1H), 4.20 (t, J=5.6 Hz, 2H), 3.12 (t, J=5.6 Hz, 2H), 2.77 (t, J=7.6 Hz, 4H), 2.73-2.65 (m, 4H), 2.28-2.21 (m, 2H), 1.96-1.85 (m, 4H). MS: m/z 418.0 (M+H ⁺ ).

Example 102 and Example 103

(S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3 -sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] Oxazine-3-sulfonimidamide:

Step 1 - Synthesis of N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonimidamide:

[661] In a solution of N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (200 mg, 0.45 mmol) in THF (12 ml ) MeONa (37 mg, 0.67 mmol) was added at 0°C under nitrogen. After 20 minutes, a solution of 3-isocyanato-2,4-diisopropyl-6-methoxypyridine (159 mg, 0.68 mmol) in THF (8 ml) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (5 ml), filtered and concentrated to dryness. The crude residue was purified by preparative TLC (EtOAc) to give N-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N'-trityl-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide (99 mg, yield: 32%) as a white solid. MS: m/z 679.3 (M+H ⁺ ).

Step 2 - Synthesis of N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide:

[662] Into a stirred solution of N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-N-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide (99 mg, 0.15 mmol) in DCM (8 ml) was added MeSO ₃ H (0.01 ml, 0.15 mmol) at 0°C. After 1 minute, the reaction mixture was made alkaline with saturated aqueous NaHCO ₃ and diluted with DCM (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative TLC (5% MeOH in dichloromethane) to give N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonidamide (60 mg, yield: 94%) as a white solid. MS: m/z 437.1 (M+H ⁺ ).

Step 3 Synthesis of (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide (Example 102 and Example 103):

[663] N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonimidamide (60 mg, 0.14 mmol) was separated using chiral SLC (Chiralpak OJ (250 mm * 30 mm, 5 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 40/60; 60 ml/ min) to give (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide (method J, 2.57 min, peak 1.9 mg, yield: 15%) and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (method J, 2.74 min, peak 2, 15.7 mg, yield: 26% ), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[664] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.00 (s, 1H), 7.49 (s, 1H), 7.24 (s, 2H), 6.45 (s, 1H), 4.42-4.34 (m, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.80 (s, 3H), 3.21-3, 15 (m, 1H), 3.04-2.97 (m, 1H), 2.19-2.11 (m, 2H), 1.10-1.00 (m, 12H). MS: m/z 437.1 (M+H ⁺ ).

[665] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.00 (s, 1H), 7.49 (s, 1H), 7.24 (s, 2H), 6.45 (s, 1H), 4.42-4.33 (m, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.80 (s, 3H), 3.21-3, 15 (m, 1H), 3.00-2.95 (m, 1H), 2.19-2.11 (m, 2H), 1.10-1.00 (m, 12H). MS: m/z 437.1 (M+H ⁺ ).

Example 104

(R,6S)-N-cyano-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia:

Step 1 - Synthesis of (R,6S)-N-cyano-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia (example 104):

Cyanogen bromide (1 M in dichloromethane, 30 µl, 30 µmol) was added to a solution of (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (10 mg, 0.02 mmol) in DMF (0.5 ml) at room temperature. After 30 minutes, saturated aqueous sodium bicarbonate (50 ml) was added and the resulting solution was directly purified by reverse phase HPLC (5-50% ACN in 0.1% NH ₄ OH (aq)) to give (R ,6S)-N-cyano-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia (4.5 mg, yield: 45%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.87 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.98 (s, 1H), 6.51 (s, 1H), 4.72-4.08 (m, 4H), 2.74 (ddd, J=30.2, 15.2, 7.9 Hz, 8H), 2.10-1.84 (m, 4H). MS: m/z 488.2 (M+H ⁺ ).

Example 105, Example 106, Example 109 and Example 110

(S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (S,7R)-N'-((1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3 ]oxazepine-3-sulfonidamide and (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5 ,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

Step 1 - Synthesis of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol:

[666] In a solution of 7-(benzyloxy)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (7.2 g, 29.47 mmol) in EtOH (72 ml) added 10% Pd (3.6 g, 3.38 mmol) on carbon. The mixture was stirred at 50°C under a hydrogen atmosphere (45 psi) for 96 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to obtain 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol (4.11 g, yield: 91%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.27 (d, J=2.0 Hz, 1H), 5.73 (d, J=2.0 Hz, 1H), 4.72 (s, 1H), 4.43-4.30 (m, 1H), 4.28-4.12 (m, 4H), 2.25-2.07 (m, 2H). MS: m/z 154.8 (M+H ⁺ ).

Step 2 - Synthesis of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl methanesulfonate:

[667] To a solution of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-ol (3.81 g, 24.71 mmol) in pyridine (38 ml) was added MsCl (3.94 g, 34.4 mmol) at room temperature under nitrogen. After 4 hours, the reaction mixture was concentrated and water (50 ml) was added. The aqueous layer was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (30 ml x 2), dried over Na ₂ SO ₄ and concentrated to give 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl methanesulfonate (5.7 g, yield: 99%) as a white solid, which was used in the next step without further purification. MS: m/z 232.9 (M+H ⁺ ).

Step 3 - Synthesis of tert-butyl (5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate:

[668] Mixture of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl methanesulfonate (2.36 g, 10.16 mmol) and NaN ₃ (1.88 g , 28.89 mmol) in DMF (25 ml) was stirred at 120°C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was directly used in the next step. MS: m/z 179.9 (M+H ⁺ ).

[669] 10% Pd (1.39 g, 13.04 mmol) on carbon, Boc ₂ O (3.33 g, 15.24 mmol) and MeOH (25 ml) were added to the reaction mixture at room temperature. The reaction mixture was left stirring under a hydrogen atmosphere (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. Water (10 ml) was added to the crude residue. The aqueous layer was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , concentrated, and the crude residue was purified using a silica gel column (0-50% EtOAc in petroleum ether) to give tert-butyl (5,6, 7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate (2.45 g, yield: 95%) as a white solid. MS: m/z 197.9 (M-56+H ⁺ ).

Step 4 - Synthesis of tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate:

[670] A solution of tert-butyl (5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate (2.45 g, 9.67 mmol) in MeCN (50 ml) NBS (2.07 g, 11.61 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness and the residue was purified using a silica gel column (0-50% EtOAc in petroleum ether) to give tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1 ,3]oxazepin-7-yl)carbamate (2.78 g, yield: 86%) as a yellow solid. MS: m/z 276.8 (M-56+H ⁺ ).

Step 5 - Synthesis of tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)(methyl)carbamate:

[671] In a solution of tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate (2.78 g, 8.35 mmol) in DMF (25 ml) was added NaH (60% in mineral oil, 0.67 g, 16.71 mmol) at 0°C under nitrogen atmosphere. After 1 hour, MeI (2.6 mL, 41.77 mmol) was added dropwise. The reaction mixture was warmed to room temperature and left stirring for an additional 16 hours. The reaction mixture was poured into water (100 ml). The aqueous layer was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (50 ml x 3), dried over Na ₂ SO ₄ and concentrated to dryness. The crude residue was purified using a silica gel column (0-33% EtOAc in petroleum ether) to give tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine- 7-yl)(methyl)carbamate (2.25 g, yield: 78%) as a white solid. MS: m/z 289.8 (M+H ⁺ ).

Step 6 - Synthesis of tert-butyl methyl(3-(N'-tritylsulfamidimidoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate:

[672] In a solution of tert-butyl (3-bromo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)(methyl)carbamate (740 mg, 2. 14 mmol) in THF (10 ml) was added dropwise n-BuLi (2.5 M in hexane, 1.06 ml, 2.64 mmol) at -78°C under nitrogen atmosphere. After 1 hour, a solution of TrtNSO (783 mg, 2.56 mmol) in THF (1.84 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 20 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.29 mL, 2.57 mmol) was added dropwise at 0°C. After 20 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated to dryness and the residue was purified using a silica gel column (0-70% EtOAc in petroleum ether) to give tert-butyl methyl (3-(N'-tritylsulfamidimidoyl)-5,6,7,8-tetrahydropyrazolo[5 ,1-b][1,3]oxazepin-7-yl)carbamate (430 mg, yield: 35%) as a yellow solid. MS: m/z 610.1 (M+Na ⁺ ).

Step 7 - Synthesis of tert-butyl (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-5,6, 7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)(methyl)carbamate:

[673] In a solution of tert-butyl methyl (3-(N'-tritylsulfamidimidoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)carbamate (330 mg , 0.56 mmol) in DMF (3 ml) and THF (15 ml) was added MeONa (46 mg, 0.84 mmol) at 0°C under nitrogen atmosphere. After 20 minutes, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (224 mg, 1.12 mmol) in THF (9 ml) was added dropwise. The reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was concentrated to dryness and the crude residue was purified by preparative TLC (50% EtOAc in petroleum ether) to give tert-butyl (3-(N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)(methyl)carbamate (316 mg, yield: 72%) as a white solid. MS: m/z 809.3 (M+Na ⁺ ).

Step 8 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[ 5,1-b][1,3]oxazepine-3-sulfonimidamide:

[674] Into a solution of tert-butyl (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-tritylsulfamidimidoyl)-5,6 ,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepin-7-yl)(methyl)carbamate (320 mg, 0.41 mmol) in DCM (20 ml) was added MeSO ₃ H (16 drops ) at 0°C. The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was adjusted to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The reaction mixture was concentrated to dryness and the crude residue was purified by preparative TLC (10% MeOH in DCM) to give N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (117 mg, yield: 65%) as a yellow solid. MS: m/z 445.1 (M+H ⁺ ).

Step 9 - Synthesis of (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6, 7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (S,7R)-N' -((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b] [1,3]oxazepine-3-sulfonidamide and (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-( methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide (Example 105, Example 106, Example 109, and Example 110):

[675] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5 ,1-b][1,3]oxazepine-3-sulfonimidamide (154 mg, 0.35 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm); supercritical CO ₂ /0.1 % EtOH + NH ₄ OH = 55/45; 80 ml/min) to obtain (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide (method I, 2.96 min, peak 1, 22, 4 mg, yield: 14%) as a white solid, (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (method I, 4.76 min, peak 4, 15.9 mg, yield : 10%) as a white solid and (7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)- 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (mixture of peaks 2 and 3, 76 mg, yield: 50%) as a white solid. (7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo [ 5,1-b][1,3]oxazepine-3-sulfonimidamide (mixture of peaks 2 and 3, 76 mg, 0.17 mmol) was separated using chiral SLC (Chiralpak OD (250 mm * 30 mm, 5 μm); supercritical CO ₂ /0.1% MeOH + NH ₄ OH = 70/30; 50 ml/min) to obtain (S,7R)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide (method K, 4.75 min, peak 2, 15.6 mg, yield: 21%) and (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (method K, 4.91 min, peak 3, 11 mg, yield : 14%), both as a white solid. Stereochemistry was randomly assigned to each stereoisomer.

[676] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.19 (s, 1H), 7.48 (s, 1H), 7.27 (s, 2H), 6. 85 (s, 1H), 4.38-4.02 (m, 4H), 2.77 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H ), 2.26 (s, 3H), 2.20-2.09 (m, 1H), 2.02-1.75 (m, 6H). MS: m/z 445.1 (M+H ⁺ ). Connection 105

[677] Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.20 (s, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 6, 85 (s, 1H), 4.43-4.05 (m, 4H), 2.77 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H ), 2.26 (s, 3H), 2.20-2.10 (m, 1H), 1.99-1.89 (m, 6H). MS: m/z 445.1 (M+H ⁺ ). Connection 109

[678] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.22 (s, 1H), 7.52 (s, 1H), 7.33 (s, 2H), 6. 86 (s, 1H), 4.40-4.30 (m, 2H), 4.26-4.04 (m, 2H), 2.77 (t, J=7.2 Hz, 4H), 2 .67 (t, J=7.2 Hz, 4H), 2.39 (s, 3H), 2.22-2.14 (m, 1H), 2.13-1.87 (m, 6H). MS: m/z 445.1 (M+H ⁺ ). Software connection

[679] Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.18 (s, 1H), 7.47 (s, 1H), 7.21 (s, 2H), 6, 85 (s, 1H), 4.30-4.03 (m, 4H), 2.77 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H ), 2.26 (s, 3H), 2.19-2.08 (m, 1H), 1.99-1.72 (m, 6H). MS: m/z 445.1 (M+H ⁺ ). Connection 106

Example 107 and Example 108

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1, 5-a]pyrimidin-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4, 5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonidamide:

Step 1 Synthesis of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine:

[680] To a stirred solution of tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (3.0 g, 9.93 mmol) in DCM (33 ml) TFA (6.6 mL, 88.56 mmol) was added at room temperature. After 1 hour, the reaction mixture was concentrated to dryness. A saturated aqueous solution of NaHCO ₃ (20 ml) was added to the crude residue. The aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with water (50 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.67 g, yield: 83%) as a yellow oil, which was used in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.24 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 4.03 (s, 1H), 3.38 (t, J=6.0 Hz, 2H), 2.20-2.13 (m, 2H).

Step 2 - Synthesis of 3-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine:

[681] To a solution of NaH (60% in mineral oil, 554 mg, 13.86 mmol) in DMF (21 ml) was added 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine ( 1.4 g, 6.93 mmol) at 0°C in a nitrogen atmosphere. After 30 minutes, MeI (0.86 mL, 13.86 mmol) was added dropwise. The reaction mixture was warmed to room temperature. After 16 hours, a saturated aqueous solution of NH ₄ Cl (50 ml) and EtOAc (100 ml) was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (100 ml), brine (50 ml), dried over Na ₂ SO ₄ filtered and concentrated to give 3-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine (1.3 g, yield: 87%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.22 (s, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.15-3.10 (m, 5H) , 2.19-2.09 (m, 2H).

Step 3 - Synthesis of 4-methyl-N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonimidamide:

[682] To a solution of 3-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.1 g, 5.09 mmol) in THF (24 ml) was added dropwise a n-BuLi (2.5 M in hexane, 2.5 ml, 6.29 mmol) at -78°C under nitrogen. After 1 hour, a solution of TrtNSO (1.86 g, 6.11 mmol) in THF (4 mL) was added dropwise. The reaction mixture was left to stir at -78°C for 20 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.7 mL, 6.19 mmol) was added dropwise at 0°C. After 20 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give 4-methyl-N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine- 3-sulfonimidamide (480 mg, yield: 21%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.46-7.41 (m, 6H), 7.16-7.10 (m, 6H), 7.07-7.02 (m, 3H), 6.73 (s, 1H), 6.41 (s, 2H), 3.80-3.70 (m, 2H), 3.27 (s, 3H), 3.02-2.99 (m, 2H), 1.94-1.85 (m, 2H).

Step 4~5 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrimidine-3-sulfonimidamide:

[683] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrimidine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-sulfonidamide (Example 100 and Example 101), replacing N'-trityl -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonimidamide on 4-methyl-N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrimidine-3-sulfonimidamide in step 3.

Step 6 - Synthesis of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-sulfonimidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- Methyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonidamide (Example 107 and Example 108):

[684] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrimidine-3-sulfonidamide (100 mg, 0.24 mmol) was separated using chiral SLC (Chiralpak AS (250 mm * 50 mm, 10 μm), supercritical CO ₂ /MeOH + 0.1% NH ₄ OH = 70/30; 70 ml/min) to obtain (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4 ,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonimidamide (method C, 3.20 min, peak 1, 27.2 mg, yield: 27%) and (R)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3 -sulfonimidamide (method C, 3.37 min, peak 2, 30.4 mg, yield: 30%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[685] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (s, 1H), 7.43 (s, 1H), 7.27 (s, 2H), 6. 86 (s, 1H), 3.96 (t, J=6.0 Hz, 2H), 3.27-3.21 (m, 5H), 2.78 (t, J=7.2 Hz, 4H ), 2.68 (t, J=7.6 Hz, 4H), 2.04-1.99 (m, 2H), 1.97-1.88 (m, 4H). MS: m/z 415.1 (M+H ⁺ ).

[686] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (s, 1H), 7.43 (s, 1H), 7.27 (s, 2H), 6. 85 (s, 1H), 3.95 (t, J=6.0 Hz, 2H), 3.27-3.20 (m, 5H), 2.77 (t, J=7.2 Hz, 4H ), 2.67 (t, J=7.6 Hz, 4H), 2.04-1.98 (m, 2H), 1.96-1.87 (m, 4H). MS: m/z 415.1 (M+H ⁺ ).

Example 111

(S,6S)-N-cyano-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia:

[687] (S,6S)-N-cyano-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano- 6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (R,6S) -6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonimidamide in step 1 (one unknown stereoisomer). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.76 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6 .94 (s, 1H), 6.51 (s, 1H), 4.72-4.08 (m, 4H), 2.74 (ddd, J=30.2, 15.2, 7.9 Hz , 8H), 2.10-1.84 (m, 4H). MS: m/z 488.2 (M+H ⁺ ).

Example 112

(R,7S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, ammonia:

[688] (R,7S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6 ,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-6-(dimethylamino)- N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (S,7S)-N'-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3] Oxazepine-3-sulfonimidamide in step 1. One unknown stereoisomer. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.85 (s, 1H), 7.37 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6 .95 (s, 1H), 6.81 (s, 1H), 4.43 (ddd, J=14.5, 5.5, 1.4 Hz, 1H), 4.31-4.11 (m , 2H), 4.01 (ddd, J=12.4, 10.2, 2.4 Hz, 1H), 3.64 (m, 1H), 2.86-2.59 (m, 8H), 2.16 (m, 2H), 1.91 (p, J=7.5 Hz, 4H). MS: m/z 471.2 (M+H ⁺ ).

Example 113 and Example 114

(S)-N'-((1-(cyclopropylmethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide and (R)-N'-((1-(cyclopropylmethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonidamide:

[689] (S)-N'-((1-(cyclopropylmethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazin-3-sulfonidamide and (R)-N'-((1-(cyclopropylmethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R)-N'-((1-(2,2-difluoroethyl)-3, 5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (S)-N'-( (1-(2,2-difluoroethyl)-3,5-diisopropyl-1H-pyrazol-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonidamide (Example 96 and Example 97) by replacing iodoethane with (bromomethyl)cyclopropane in Step 3. After preparative HPLC and preparative SLC (Step 6), two isomers with unknown absolute stereochemistry were isolated, peak 1 (Method T, 1, 02 min) and peak 2 (method T, 1.74 min).

[690] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (s, 1H), 7.48 (s, 1H), 7.22 (s, 2H), 4.50- 4.21 (m, 2H), 4.09 (t, J=6.1 Hz, 2H), 3.79 (d, J=6.7 Hz, 2H), 2.82-2.64 (m , 2H), 2.28-2.08 (m, 2H), 1.17 (d, J=7.1 Hz, 6H), 1.09 (dt, J=6.9, 3.1 Hz, 7H), 0.56-0.38 (m, 2H), 0.38-0.22 (m, 2H). MS: m/z 450.3 (M+H ⁺ ).

[691] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (s, 1H), 7.48 (s, 1H), 7.21 (s, 2H), 4.45- 4.29 (m, 2H), 4.09 (t, J=6.1 Hz, 2H), 3.79 (d, J=6.7 Hz, 2H), 2.80-2.63 (m , 2H), 2.17 (m, 2H), 1.18 (m, 6H), 1.16-0.99 (m, 7H), 0.54-0.38 (m, 2H), 0, 30 (dt, J=4.9, 2.9 Hz, 2H). MS: m/z 450.2 (M+H ⁺ ).

Example 115 and Example 116

N-((S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide and N-((R,6S)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide:

Step 1 - Synthesis of N-((S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide and N-((R,6S)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide (Example 115 and Example 116):

[692] In a solution of (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (180 mg, 0.4171 mmol) in dichloromethane (8 ml) was added triethylamine (1.16 ml, 8.343 mmol) and acetic anhydride (0 .39 ml, 4.171 mmol) at 0°C. After addition, the reaction mixture was allowed to slowly warm to room temperature. After 1.5 hours, additional trimethylamine (1.16 mL, 8.343 mmol) and acetic anhydride (0.39 mL, 4.171 mmol) were added. After additional stirring for 1.5 hours, the reaction mixture was directly subjected to flash column chromatography (silica, 100% dichloromethane, then a gradient of DCM/MeOH/H ₂ O/MH ₄ OH (90/10/0.6/0.6 )) with obtaining the required product. The material was further purified using a chiral column (2.1 × 25.0 cm (S,S) Whelk0-1 from Regis Technologies (Morton Grove, IL) and an isocratic method using CO ₂ and 45% ethanol with 0.25% ammonium hydroxide at 100 bar and 25°C) to obtain N-((R,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidoyl)acetamide (peak 1, method W, 1.3 min, 32 mg, yield: 16 %) and N-((S,6S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoyl)acetamide (peak 2, method W, 2.2 min, 13 mg, yield: 7%). Stereochemistry was randomly assigned to each stereoisomer.

[693] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.57-7.51 (m, 1H), 7.46 (dd, J=6 .7, 4.0 Hz, 1H), 6.84 (s, 1H), 4.54 (d, J=11.5 Hz, 1H), 4.29 (d, J=11.5 Hz, 1H ), 4.23 (dd, J=13.2, 3.7 Hz, 1H), 4.14 (d, J=13.2 Hz, 1H), 4.01 (s, 1H), 3.35 (d, J=1.4 Hz, 4H), 2.77 (t, J=7.4 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 1.99-1 .89 (m, 4H), 1.86 (d, J=2.9 Hz, 3H). MS: m/z 474.2 (M+H ⁺ ). Connection 116

Peak 2: ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.70 (s, 1H), 8.33 (s, 1H), 7.79-7.51 (m, 1H), 6.88 (s, 1H), 4.61 (d, J=11.8 Hz, 1H), 4.33 (d, J=11.7 Hz, 1H), 4.26 (dd, J=13.3, 3.5 Hz, 1H), 4.18 (d, J=13.4 Hz, 1H), 4.05 (s, 1H), 3.36 (s, 3H), 2.79 (t, J= 7.4 Hz, 4H), 2.69 (d, J=7.9 Hz, 4H), 2.03-1.88 (m, 7H). MS: m/z 474.2 (M+H ⁺ ). Connection 115

Example 117 and Example 118

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1,5-d] [1,4]oxazepine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7 ,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonimidamide:

Step 1 - Synthesis of ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)acetate and ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-3-yl)acetate:

[694] To a solution of ethyl 2-(1H-pyrazol-5-yl)acetate (10.0 g, 64.86 mmol) in DCM (300 ml) was added 3,4-dihydro-2H-pyran (11 g, 129 .73 mmol) and TsOH (3.21 g, 16.86 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole -5-yl)acetate and ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetate (12 g, yield: 77.6%) as a colorless oil. MS: m/z 239.2 (M+H ⁺ ).

Step 2 - Synthesis of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)ethanol and 2-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl)ethanol:

[695] A solution of ethyl _2- (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 5-yl)acetate and ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetate (12 g, 50.36 mmol) in THF (100 ml) at 0 °C. After addition, the reaction mixture was warmed to room temperature. After 3 hours, the reaction mixture was cooled to 0°C and a saturated aqueous Na ₂ SO ₄ solution was slowly added to quench the reaction. The mixture was dried over Na ₂ SO ₄ . Solids were removed by filtration and the filtrate was concentrated to dryness to give a mixture of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)ethanol and 2-(1-(tetrahydro-2H -pyran-2-yl)-1H-pyrazol-3-yl)ethanol (7 g, crude), which was used in the next step without further purification. MS: m/z 197.0 (M+H ⁺ ).

Step 3 - Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-5-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-pyrazole and 1 -(tetrahydro-2H-pyran-2-yl)-3-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-pyrazole:

[696] Into a solution of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)ethanol and 2-(1-(tetrahydro-2H-pyran-2-yl)-1H -pyrazol-3-yl)ethanol (7 g, 35.67 mmol) in DMF (150 ml) was added NaH (60% in mineral oil, 2.1 g, 53.5 mmol) at 0°C. After 30 minutes, 2-(2-bromoethoxy)tetrahydropyran (22.3 g, 107.01 mmol) was added. The reaction mixture was warmed to room temperature. After 32 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (50 ml). The aqueous layer was extracted with DCM (3 x 300 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to give a mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(2-(2-((tetrahydro-2H-pyran -2-yl)oxy)ethoxy)ethyl)-1H-pyrazole and 1-(tetrahydro-2H-pyran-2-yl)-3-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy)ethoxy)ethyl)-1H-pyrazole (4.8 g, yield: 41%) as a colorless oil. MS: m/z 325.1 (M+H ⁺ ).

Step 4 - Synthesis of 2-(2-(1H-pyrazol-5-yl)ethoxy)ethanol:

[697] In a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-pyrazole and 1-(tetrahydro-2H-pyran-2-yl)-3-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-pyrazole (4.8 g, 7.4 mmol) in EtOH (80 ml) was added concentrated HCl (7.0 ml, 84 mmol) at 0°C. After addition, the reaction mixture was heated to 30°C. After 16 hours, the reaction mixture was concentrated to dryness. A saturated aqueous solution of NaHCO ₃ was added to the crude residue to bring the solution to pH=8. The resulting mixture was extracted with DCM (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude residue was purified by silica gel column chromatography (MeOH/DCM = 1:10) to obtain 2-(2-(1H-pyrazol-5-yl)ethoxy)ethanol (2 g, yield: 86%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=12.45 (s, 1H), 7.50-7.20 (m, 1H), 6.07 (s, 1H), 4.62 ( s, 1H), 3.61 (t, J=7.2 Hz, 2H), 3.52-3.46 (m, 2H), 3.44-3.40 (m, 2H), 2.83 -2.74 (m, 2H).

Step 5 Synthesis of 2-(2-(1H-pyrazol-5-yl)ethoxy)ethyl methanesulfonate:

[698] Into a stirred solution of 2-(2-(1H-pyrazol-5-yl)ethoxy)ethanol (2.0 g, 12.81 mmol) and triethylamine (5.3 mL, 38.42 mmol) in DCM ( 60 ml) MsCl (1.0 ml, 12.81 mmol) was added at 0°C. After 1 hour, water (2 ml) was added. The aqueous layer was extracted with DCM (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give 2-(2-(1H-pyrazol-5-yl)ethoxy)ethyl methanesulfonate (1.1 g, yield: 26%) as colorless oil. MS: m/z 234.9 (M+H ⁺ ).

Step 6 Synthesis of 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine:

[699] To a solution of 2-(2-(1H-pyrazol-5-yl)ethoxy)ethyl methanesulfonate (1.1 g, 4.7 mmol) in DMF (18 ml) was added NaH (60% in mineral oil, 226 mg, 5.63 mmol) at 0°C. The reaction mixture was warmed to room temperature. After 12 hours, the reaction mixture was cooled to 0°C and a saturated aqueous solution of NH ₄ Cl (3 ml) was added. The reaction mixture was concentrated to dryness and the crude residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine ( 480 mg, yield: 70%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.33 (d, J=1.6 Hz, 1H), 6.05 (d, J=1.6 Hz, 1H), 4.45-4 .42 (m, 2H), 3.90-3.87 (m, 2H), 3.86-3.83 (m, 2H), 3.01-2.98 (m, 2H).

Step 7 - Synthesis of 3-bromo-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine:

[700] To a solution of 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine (480 mg, 3.47 mmol) in MeCN (15 ml) was added NBS (618 mg, 3. 47 mmol) at 0°C. The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to give 3-bromo-4,5,7,8-tetrahydropyrazolo[1,5-d][1 ,4]oxazepine (420 mg, yield: 56%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.35 (s, 1H), 4.43 (t, J=4.0 Hz, 2H), 3.90-3.84 (m, 4H) , 2.99 (t, J=4.8 Hz, 2H).

Step 8 - Synthesis of N'-trityl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonimidamide:

[701] To a solution of 3-bromo-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine (200 mg, 0.92 mmol) in THF (4 ml), n was added dropwise -BuLi (2.5 M in hexane, 0.41 ml, 1.01 mmol) at -78°C under nitrogen. After 1 hour, a solution of TrtNSO (310 mg, 1.01 mmol) in THF (1 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 30 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.11 mL, 0.99 mmol) was added dropwise at 0°C. After 30 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-80% EtOAc in petroleum ether) to give N'-trityl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4 ]oxazepine-3-sulfonimidamide (200 mg, yield: 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.42-7.30 (m, 6H), 7.18-7.12 (m, 6H), 7.10-7.07 (m, 4H), 6.5 (s, 2H), 4.25-4.19 (m, 2H), 3.71-3.59 (m, 4H), 3.08-3.03 (m, 2H) .

Step 9 - Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-4,5,7,8-tetrahydropyrazolo[1, 5-d][1,4]oxazepine-3-sulfonimidamide:

[702] Into a stirred solution of N'-trityl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonidamide (100 mg, 0.22 mmol) in THF (5 ml) MeONa (24 mg, 0.44 mmol) was added at 0°C. After 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (52 mg, 0.26 mmol) was added and the reaction mixture was warmed to room temperature. After 16 hours, MeOH (1 ml) was added and the reaction mixture was concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N' -Trityl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonidamide (100 mg, yield: 70%) as a white solid.

Step 10 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1,5-d] [1,4]oxazepine-3-sulfonimidamide:

[703] Into a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-trityl-4,5,7,8-tetrahydropyrazolo [1 ,5-d][1,4]oxazepine-3-sulfonidamide (200 mg, 0.3 mmol) in DCM (10 ml) was added MeSO ₃ H (6 drops) at 0°C. After addition, the reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was adjusted to pH=8 by adding a saturated aqueous solution of NaHCO ₃ . The reaction mixture was concentrated to dryness and the crude residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to give N'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonimidamide (100 mg, yield: 79%) as a white solid. MS: m/z 416.1 (M+H ⁺ ).

Step 11 - Synthesis of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1, 5-d][1,4]oxazepine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4 ,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonidamide (Example 117 and Example 118):

[704] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1,5-(1] [1,4]oxazepine-3-sulfonimidamide (100 mg, 0.24 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 50 mm, 10 μm); supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 45/55; 80 ml/min) to give (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5 ,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepine-3-sulfonimidamide (method E, 2.30 min, peak 1, 12.9 mg, yield: 12%) and (R)- N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4 ]oxazepine-3-sulfonimidamide (method E, 2.92 min, peak 2, 11.8 mg, yield: 11%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[705] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.17 (s, 1H), 7.62 (s, 1H), 7.32 (s, 2H), 6. 85 (s, 1H), 4.47-4.38 (m, 2H), 3.78-3.66 (m, 4H), 3.21-3.16 (m, 2H), 2.76 ( t, J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 1.96-1.88 (m, 4H). MS: m/z 416.1 (M+H ⁺ ).

[706] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.20 (s, 1H), 7.63 (s, 1H), 7.38 (s, 2H), 6, 85 (s, 1H), 4.43 (t, J=4.0 Hz, 2H), 3.80-3.64 (m, 4H), 3.29-3.28 (m, 1H), 3 ,23-3.14 (m, 1H), 2.76 (t, J=7.2 Hz, 4H), 2.64 (t, J=6.8 Hz, 4H), 1.99-1, 86 (m, 4H). MS: m/z 416.1 (M+H ⁺ ).

Example 119 and Example 120

(S)-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazin-3-sulfonidamide and (R)-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

Step 1 - Synthesis of 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine:

[707] In a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) aniline (synthesized according to WO 2019008025, 240 mg, 0.92 mmol) and triethylamine (0.35 ml, 2.49 mmol) in THF (12 ml) was added triphosgene (109 mg, 0.37 mmol) at room temperature under nitrogen atmosphere. The mixture was heated to 70°C. After 1 hour, the reaction mixture was cooled to room temperature and filtered through a pad of silica gel. The silica gel layer was washed with THF (5 mL x 3). The filtrate containing 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine was used directly as a solution in THF in the next step.

Stage 2 Synthesis of N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonimidamide:

[708] N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 102 and Example 103), replacing 3-isocyanato-2,4-diisopropyl-6-methoxypyridine with 4-(5- fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine in step 1.

Step 3 Synthesis of (S)-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-3-sulfonidamide and (R)-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 119 and Example 120):

[709] N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonidamide (107 mg, 0.22 mmol) was separated using chiral SLC (Chiralpak 1C (250 mm * 30 mm, 10 μm), CO ₂ /EtOH + 0.1% NH ₄ OH = 40 /60; 80 ml/min) to obtain (S)-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (method L, 3.63 min, peak 1, 32 mg, yield: 29%) and (R)-N'-((4 -fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide ( method L, 6.88 min, peak 2, 38 mg, yield: 34%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[710] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.18-8.10 (m, 2H), 7.27 (s, 1H), 7.18-7.12 (m, 3H), 7.00-6.90 (m, 2H), 6.79 (s, 1H), 4.36-4.30 (m, 2H), 4.09 (t, J=6 .4 Hz, 2H), 3.87 (s, 3H), 3.15-3.08 (m, 1H), 2.20-2.12 (m, 2H), 1.11-1.05 ( m, 6H). MS: m/z 489.1 (M+H ⁺ ).

[711] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.16-8.08 (m, 2H), 7.27 (s, 1H), 7.20-7.10 (m, 3H), 7.00-6.90 (m, 2H), 6.79 (s, 1H), 4.38-4.31 (m, 2H), 4.10 (t, J=6 .4 Hz, 2H), 3.87 (s, 3H), 3.15-3.06 (m, 1H), 2.20-2.12 (m, 2H), 1.13-1.06 ( m, 6H). MS: m/z 489.1 (M+H ⁺ ).

Example 121

(S,7R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, ammonia:

[712] (S,7R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6 ,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-6-(dimethylamino)- N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (R,7R)-N'-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3] oxazepine-3-sulfonimidamide in step 1 (one unknown stereoisomer). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.86 (s, 1H), 7.39 (s, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 6 .96 (s, 1H), 6.82 (s, 1H), 4.44 (ddd, J=14.5, 5.5, 1.4 Hz, 1H), 4.27-4.13 (m , 2H), 4.02 (ddd, J=12.4, 10.2, 2.4 Hz, 1H), 3.65 (k, J=4.3, 3.1 Hz, 1H), 3, 27 (s, 3H), 2.87-2.61 (m, 8H), 2.15 (ddd, J=16.7, 7.9, 3.7 Hz, 2H), 2.03-1, 81 (m, 4H). MS: m/z 471.2 (M+H ⁺ ).

Example 122

(R,7R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, ammonia:

[713] (R,7R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6 ,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-6-(dimethylamino)- N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (S,7R)-N'-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3] oxazepine-3-sulfonimidamide in step 1 (one unknown stereoisomer). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.83 (s, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6 .94 (s, 1H), 6.82 (s, 1H), 4.51-4.37 (m, 1H), 4.28-4.15 (m, 2H), 4.10 (ddd, J =12.3, 8.4, 4.0 Hz, 1H), 3.65 (k, J=4.5 Hz, 1H), 3.27 (s, 3H), 2.76 (m, 4H) , 2.72-2.57 (m, 4H), 2.14 (dt, J=8.3, 3.8 Hz, 2H), 2.01-1.84 (m, 4H). MS: m/z 471.2 (M+H ⁺ ).

Example 123

(S,7S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7, 8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, ammonia:

[714] (S,7S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6 ,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, ammonia was prepared using the general procedure described for the preparation of (R,6S)-N-cyano-6-(dimethylamino)- N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide (Example 104), replacing (S,6S)-6-(dimethylamino)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide on (R,7S)-N'-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-methoxy-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3] oxazepine-3-sulfonimidamide in step 1 (one unknown stereoisomer). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.80 (s, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6 .94 (s, 1H), 6.81 (s, 1H), 4.44-4.37 (m, 1H), 4.26-4.15 (m, 2H), 4.09 (ddd, J =12.3, 8.6, 3.9 Hz, 1H), 3.27 (s, 3H), 2.76 (m, 4H), 2.68 (m, 4H), 2.14 (dt, J=8.9, 4.1 Hz, 2H), 2.02-1.80 (m, 4H). MS: m/z 471.2 (M+H ⁺ ).

Example 124 and Example 125

(R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazol-7- sulfonidamide and (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazol- 7-sulfonimidamide:

Step 1 Synthesis of N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide:

[715] n-BuLi (2.5 M in hexane, 0.51 ml, 1.27 mmol) at -78°C in an N ₂ atmosphere. After 1 hour, a solution of TrtNSO (388 mg, 1.27 mmol) in THF (1 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 20 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.15 mL, 1.33 mmol) was added dropwise at 0°C. After 20 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to give N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (140 mg, yield: 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.43 (d, J=7.6 Hz, 6H), 7.22-7.13 (m, 6H), 7.13-7.06 (m, 3H), 7.04 (s, 1H), 6.38 (s, 2H), 5.03 (t, J=8.0 Hz, 2H), 4.18-4.07 (m, 2H).

Step 2~3 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazol- 7-sulfonimidamide:

[716] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide prepared using the general procedure described for the preparation of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide (Example 100 and Example 101), replacing N'-trityl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide to N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide in step 3.

Step 4 Synthesis of (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole -7-sulfonidamide and (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b ]oxazole-7-sulfonidamide (example 124 and example 125):

[717] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (53 mg, 0.14 mmol) were separated using chiral SLC (Chiralcel OD (250 mm * 30 mm, 5 μm); supercritical CO ₂ /MeOH + 0.1% NH ₄ OH = 40/60; 50 ml/min ) to give (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole -7-sulfonimidamide (method M, 5.71 min, peak 1, 4.8 mg, yield: 9%) and (S)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (method M, 6.07 min, peak 2, 6.3 mg, yield: 11%) , both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[718] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.54 (s, 1H), 7.33 (s, 2H), 6, 86 (s, 1H), 5.23-5.16 (m, 2H), 4.34 (t, J=8.4 Hz, 2H), 2.78 (t, J=7.2 Hz, 4H ), 2.72-2.66 (m, 4H), 1.99-1.89 (m, 4H). MS: m/z 388.1 (M+H ⁺ ).

[719] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.20 (s, 1H), 7.54 (s, 1H), 7.33 (s, 2H), 6. 86 (s, 1H), 5.23-5.16 (m, 2H), 4.33 (t, J=8.4 Hz, 2H), 2.77 (t, J=7.2 Hz, 4H ), 2.70-2.64 (m, 4H), 1.99-1.89 (m, 4H). MS: m/z 388.0 (M+H ⁺ ).

Example 126, Example 127, Example 128 and Example 129

(S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S)-N'-(((S)-3-metal-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide, (R)-N'-(((R) -3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide and (R)-N'-(((S)-3-mectyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

Step 1 - Synthesis of methylene-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene:

[720] To a solution of methyltriphenylphosphonium bromide (18.5 g, 51.8 mmol) in THF (180 ml), a solution of t-BuOK (1.0 M in THF, 41.4 ml, 41.48 mmol) was added dropwise at 0°C in a nitrogen atmosphere. After 2 hours, a solution of 8-nitro-3,5,6,7-tetrahydro-2H-s-indacen-1-one (4.5 g, 20.7 mmol) in THF (27 ml) was added dropwise. After addition, the reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was quenched with water (80 ml). The aqueous layer was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (80 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (2% EtOAc in petroleum ether) to give methylene-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (2.1 g, 47% yield ) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.23 (s, 1H), 5.24 (s, 1H), 5.20 (s, 1H), 2.97-2.91 (m, 6H), 2.89-2.83 (m, 2H), 2.21-2.10 (m, 2H).

Step 2 - Synthesis of 3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-amine:

[721] Mixture of methylene-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (2.1 g, 9.76 mmol) and 10% Pd/C on carbon (1.04 g, 0.98 mmol) in EtOH (147 ml) was stirred at room temperature under a hydrogen atmosphere (15 psi). After 16 hours, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated and the crude residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give 3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-amine ( 800 mg, 44% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ=6.61 (s, 1H), 3.53 (s, 2H), 3.24-3.14 (m, 1H), 3.06-2, 93 (m, 1H), 2.91-2.83 (m, 2H), 2.80-2.62 (m, 3H), 2.35-2.23 (m, 1H), 2.17- 2.06 (m, 2H), 1.83-1.73 (m, 1H), 1.21 (d, J=6.8 Hz, 3H).

Step 3 - Synthesis of 8-isocyanato-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene:

[722] In a solution of 3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (306 mg, 1.63 mmol) and triethylamine (0.61 ml, 4.41 mmol) in THF (20 ml) was added triphosgene (194 mg, 0.65 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through a pad of silica gel. The silica gel layer was washed with THF (5 mL x 3). The filtrate containing 8-isocyanato-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene was used directly as a solution in THF in the next step.

Step 4~5 - Synthesis of N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonidamide:

[723] N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazin-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6. 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 102 and Example 103), replacing 3-isocyanato-2,4-diisopropyl-6-methoxypyridine with 8-isocyanato-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene in step 1.

Step 6 - Synthesis of (S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S)-N'-(((S)-3-methyl-1,2,3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide, (R)-N'-( ((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide and (R)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 126, Example 127, Example 128 and Example 129):

[724] N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonidamide (116 mg, 0.28 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 50 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1 % NH ₄ OH = 65/35; 70 ml/min) to obtain (S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene -4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method I, 2.58 min, peak 1, 7 mg, yield : 6%), (S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (method I, 3.30 min, peak 2, 7 mg, yield: 6%), (R)-N' -(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide (method I, 3.86 min, peak 3.9 mg, yield: 7%) and (R)-N'-(((S)-3-methyl- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonimidamide (method I, 4.32 min, peak 4.8 mg, yield: 6%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[725] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.08 (s, 1H), 7.49 (s, 1H), 7.19 (s, 2H), 6, 83 (s, 1H), 4.40-4.33 (m, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.88-2.60 (m, 7H), 2 ,18-2.05 (m, 3H), 1.97-1.85 (m, 2H), 1.60-1.52 (m, 1H), 1.03 (d, J=6.8 Hz , 3H). MS: m/z 416.1 (M+H ⁺ ).

[726] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.10 (s, 1H), 7.49 (s, 1H), 7.18 (s, 2H), 6, 84 (s, 1H), 4.40-4.35 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.85-2.60 (m, 7H), 2 ,19-2.06 (m, 3H), 1.95-1.85 (m, 2H), 1.58-1.52 (m, 1H), 1.04 (d, J=6.8 Hz , 3H). MS: m/z 416.2 (M+H ⁺ ).

[727] Peak 3: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.09 (s, 1H), 7.49 (s, 1H), 7.18 (s, 2H), 6, 84 (s, 1H), 4.40-4.33 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.85-2.60 (m, 7H), 2 .19-2.09 (m, 3H), 1.95-1.85 (m, 2H), 1.60-1.52 (m, 1H), 1.04 (d, J=6.8 Hz , 3H). MS: m/z 416.1 (M+H ⁺ ).

[728] Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.09 (s, 1H), 7.49 (s, 1H), 7.22 (s, 2H), 6, 84 (s, 1H), 4.40-4.34 (m, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.86-2.60 (m, 7H), 2 .16-2.07 (m, 3H), 1.97-1.89 (m, 2H), 1.58-1.52 (m, 1H), 1. 1.03 (d, J=6, 8 Hz, 3H). MS: m/z 416.1 (M+H ⁺ ).

Example 130, Example 131 and Example 132

(S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide and (6S)-N'-((1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine -3-sulfonimidamide:

Step 1~8 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide:

[729] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5 ,1-b][1,3]oxazepine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide, (R,7S)-N '-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo [5,1-b ][1,3]oxazepine-3-sulfonidamide, (S,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7- (methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide and (R,7R)-N'-((1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-7-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide ( example 105, example 106, example 109 and example 110), replacing 7-(benzyloxy)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine with 6-(benzyloxy)-5 ,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine in step 1.

Step 9 - Synthesis of (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6, 7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide, (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide and (6S)-N'-( (1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1 ,3]oxazepine-3-sulfonimidamide (Example 130, Example 131 and Example 132):

[730] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5 ,1-b][1,3]oxazepine-3-sulfonimidamide (72 mg, 0.16 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 5 μm), supercritical CO ₂ /EtOH + 0 ,1% NH ₄ OH=40/60; 60 ml/min) to obtain (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonimidamide (method N, 6.56 min, peak 1, 11, 2 mg, yield: 16%), (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino) -5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine-3-sulfonidamide (method N, 7.11 min, peak 2, 2.9 mg, 4% yield) and ( 6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-5,6,7,8-tetrahydropyrazolo[5 ,1-b][1,3]oxazepine-3-sulfonimidamide (method N, 7.37 min, peak 3, 4.3 mg, yield: 6%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[731] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (s, 1H), 7.50 (s, 1H), 7.31 (s, 2H), 6.85 ( s, 1H), 4.39-4.29 (m, 1H), 4.20-4.14 (m, 1H), 4.11-4.01 (m, 1H), 3.94-3, 82 (m, 1H), 2.92-1.86 (s, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.68-2.65 (m, 4H), 2 .33 (s, 3H), 1.97-1.85 (m, 5H), 1.74-1.60 (m, 1H). MS: m/z 445.1 (M+H ⁺ ).

[732] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.24 (s, 1H), 7.51 (s, 1H), 7.32 (s, 2H), 6.86 ( s, 1H), 4.41-4.32 (m, 1H), 4.26-4.19 (m, 1H), 4.14-4.03 (m, 1H), 3.97-3, 85 (m, 1H), 2.95-2.90 (m, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.69-2.66 (m, 4H), 2 .37 (s, 3H), 1.98-1.88 (m, 5H), 1.77-1.64 (m, 1H). MS: m/z 445.3 (M+H ⁺ ).

[733] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.25 (s, 1H), 7.50 (s, 1H), 7.31 (s, 2H), 6, 85 (s, 1H), 4.41-4.30 (m, 1H), 4.23-4.13 (m, 1H), 4.10-4.00 (m, 1H), 3.91- 3.77 (m, 1H), 2.92-1.86 (s, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.68-2.64 (m, 4H) , 2.33 (s, 3H), 1.99-1.87 (m, 5H), 1.76-1.62 (m, 1H). MS: m/z 445.2 (M+H ⁺ ).

Example 133 and Example 134

(S)-4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyridin-3-sulfonidamide and (R)-4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide:

Step 1 Synthesis of 6',7'-dihydro-5'H-spiro[[1,3]dithiolane-2,4'-pyrazolo[1,5-a]pyridine]:

[734] To a solution of 6,7-dihydro-5H-pyrazolo[1,5-a]pyridin-4-one (4.0 g, 29.4 mmol) in DCM (168 ml) was added 1,2-ethanedithiol ( 3.7 mL, 44.0 mmol) and boron trifluoride acetic acid complex (6.1 mL, 43.8 mmol) at room temperature. After 48 hours, the reaction mixture was quenched with water (200 ml). The aqueous layer was extracted with DCM (200 ml x 3). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 6',7'-dihydro-5'H-spiro[[1,3]dithiolane-2,4'-pyrazolo[1, 5-a]pyridine] (4.2 g, yield: 67%) as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.43 (d, J=2.0 Hz, 1H), 6.40 (d, J=2.0 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 3.58-3.53 (m, 2H), 3.48-3.34 (m, 2H), 2.42 (t, J=6.0 Hz, 2H ), 2.28-2.22 (m, 2H). MS: m/z 212.9 (M+H ⁺ ).

Step 2 - Synthesis of 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine:

[735] To a solution of 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (23.0 g, 80.4 mmol) in DCM (46 ml), HF-pyridine (38 ml, 421 .8 mmol) at -78°C, and after it - 6',7'-dihydro-5'H-spiro[[1,3]dithiolane-2,4'-pyrazolo[1,5-a]pyridine] (4.2 g, 19.8 mmol). After 4 hours, the reaction mixture was warmed to 0°C and left to stir for an additional 1 hour. The reaction mixture was quenched with water (100 ml). The aqueous layer was extracted with DCM (2 x 100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (3, 13 g, yield: 67%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.48 (s, 1H), 4.20 (t, J=6.0 Hz, 2H), 2.43-2.34 (m, 2H), 2.27-2.21 (m, 2H). MS: m/z 236.9 (M+H ⁺ ).

Step 3 - Synthesis of 4,4-difluoro-N'-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimide amide:

[736] To a solution of 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (400 mg, 1.69 mmol) in THF (8 ml) was added dropwise n-BuLi (2.5 M in hexane, 0.84 ml, 2.1 mmol) at -78°C under nitrogen. After 1 hour, a solution of TrtNSO (618 mg, 2.02 mmol) in THF (8 ml) was added dropwise. The reaction mixture was left to stir at -78°C for 20 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes. Tert-butyl hypochlorite (0.24 mL, 2.12 mmol) was added at 0°C. After 20 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0:70% EtOAc in petroleum ether) to give 4,4-difluoro-N-trityl-4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-3-sulfonidamide (315 mg, yield: 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.43-7.39 (m, 6H), 7.18-7.15 (m, 6H), 7.14-7.08 (m , 3H), 6.33 (s, 2H), 4.16-4.09 (m, 2H), 2.40-2.32 (m, 2H), 2.10-2.04 (m, 2H ). MS: m/z 501.1 (M+Na ⁺ ).

Step 4-5 - Synthesis of 4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide:

[737] 4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide (Example 100 and Example 101), replacing N '-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide on 4,4-difluoro-N'-trityl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide in step 3.

Step 6 - Synthesis of (S)-4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6, 7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonidamide and (R)-4,4-difluoro-H'-((1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonidamide (Example 133 and Example 134):

[738] 4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-3-sulfonimidamide (78 mg, 0.18 mmol) was separated using chiral SLC (Chiralpak AS (250 mm * 30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH=65/35; 70 ml/min) to obtain (S)-4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonimidamide (method C, 3.31 min, peak 1, 11.1 mg, yield: 14%) and (R) -4,4-difluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyridine-3-sulfonimidamide (Method C, 3.55 min, peak 2, 14.5 mg, yield: 18%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[739] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.85 (s, 1H), 7.41 (s, 2H), 6, 85 (s, 1H), 4.26 (t, J=6.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 2.48-2.40 (m, 2H), 2.17-2.10 (m, 2H), 1.95-1.88 (m, 4H). MS: m/z 436.1 (M+H ⁺ ).

[740] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.85 (s, 1H), 7.41 (s, 2H), 6. 85 (s, 1H), 4.26 (t, J=6.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 4H), 2.67 (t, J=6.8 Hz, 4H), 2.48-2.40 (m, 2H), 2.17-2.10 (m, 2H), 1.96-1.86 (m, 4H). MS: m/z 436.1 (M+H ⁺ ).

Example 135, Example 136, Example 137 and Example 138

(S)-6,6-dimethyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S)-6,6-dimethyl-N'-(((S)-3-methyl-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide, (R)-6,6-dimethyl-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R)-6,6-dimethyl-N'-(((R)-3-methyl-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide:

Step 1~2 - Synthesis of 6,6-dimethyl-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[741] 6,6-dimethyl-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl )carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S)-N'-((2,4- diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 76 and Example 77), replacing 3-isocyanato-2,4-diisopropyl-6-methoxy-pyridine with 8-isocyanato-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene in step 3.

Step 3 - Synthesis of (S)-6,6-dimethyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S)-6,6-dimethyl-N'-(((S)-3- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonidamide, (R)-6,6-dimethyl-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R)-6,6-dimethyl-N'-(((R)-3- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide (Example 135, Example 136, Example 137 and Example 138):

[742] 6,6-dimethyl-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (95 mg, 0.21 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm), supercritical CO ₂ /MeOH + 0.1% NH ₄ OH = 40/60; 70 ml/min) to obtain (S)-6,6-dimethyl-N'-(((R)-3-methyl-1,2,3 ,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (method O, 5.58 min, peak 1, 17.8 mg, yield: 19%), (S)-6,6-dimethyl-N'-(((S)-3-methyl-1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method O, 6.28 min, peak 2, 12.9 mg, yield: 13%), (R)-6,6-dimethyl-N'-(((S)-3-methyl-1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method O, 7.67 min, peak 3, 18.4 mg, yield: 19%) and (R)-6,6-dimethyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method O, 8.39 min, peak 4, 12 .7 mg, yield: 13%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[743] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.04 (s, 1H), 7.52 (s, 1H), 7.24 (s, 2H), 6.83 ( s, 1H), 4.05 (s, 2H), 3.85 (s, 2H), 2.89-2.73 (m, 4H), 2.70-2.55 (m, 3H), 2 .17-2.05 (m, 1H), 1.98-1.85 (m, 2H), 1.60-1.49 (m, 1H), 1.05-1.01 (m, 9H) . MS: m/z 444.1 (M+H ⁺ ).

[744] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.06 (s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 6. 84 (s, 1H), 4.06 (s, 2H), 3.86 (s, 2H), 2.89-2.73 (m, 4H), 2.70-2.55 (m, 3H) , 2.17-2.05 (m, 1H), 1.98-1.85 (m, 2H), 1.60-1.49 (m, 1H), 1.06-1.01 (m, 9H). MS: m/z 444.1 (M+H ⁺ ).

[745] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.06 (s, 1H), 7.52 (s, 1H), 7.25 (s, 2H), 6.83 ( s, 1H), 4.08 (s, 2H), 3.83 (s, 2H), 2.89-2.73 (m, 4H), 2.70-2.55 (m, 3H), 2 .17-2.07 (m, 1H), 1.99-1.84 (m, 2H), 1.60-1.50 (m, 1H), 1.06-1.00 (m, 9H) . MS: m/z 444.1 (M+H ⁺ ).

[746] Peak 4: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.07 (s, 1H), 7.52 (s, 1H), 7.25 (s, 2H), 6. 84 (s, 1H), 4.05 (s, 2H), 3.86 (s, 2H), 3.28-3.25 (m, 1H), 2.87-2.72 (m, 4H) , 2.70-2.51 (m, 2H), 2.15-2.07 (m, 1H), 1.99-1.85 (m, 2H), 1.61-1.53 (m, 1H), 1.06-1.01 (m, 9H). MS: m/z 444.1 (M+H ⁺ ).

Example 139 and Example 140

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1- b]oxazole-7-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2, 3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide:

Step 1 - Synthesis of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate:

[747] To a solution of 1H-pyrazol-3(2H)-one (20.0 g, 238 mmol) in DCM (300 ml) was added triethylamine (37 ml, 267 mmol) at 0°C. After 10 minutes, Boc ₂ O (57.11 g, 262 mmol) in DCM (100 ml) was added dropwise. After addition, the reaction mixture was warmed to room temperature and left stirring for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was dissolved in water (100 ml). The aqueous layer was extracted with EtOAc (200 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (2.8 g, yield: 6%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.92 (s, 1H), 7.97 (d, J=3.2 Hz, 1H), 5.89 (d, J=2, 8 Hz, 1H), 1.53 (s, 9H).

Step 2 - Synthesis of tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-1-carboxylate:

[748] To a solution of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (2.8 g, 15.2 mmol) in MeCN (56 ml) was added K ₂ CO ₃ (4.2 g, 30.4 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was heated at 80°C. After 1 hour, ethyl 2-bromo-2-methylpropanoate (3.0 g, 15.2 mmol) was added and the mixture was left stirring at 80°C for an additional 16 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazol-1- carboxylate (3.1 g, yield: 68%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.84 (d, J=2.8 Hz, 1H), 5.87 (d, J=3.2 Hz, 1H), 4.22 (k , J=6.8 Hz, 2H): 1.70 (s, 6H), 1.59 (s, 9H), 1.23 (t, J=7.2 Hz, 3H).

Step 3 - Synthesis of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol:

[749] To a suspension of LiAlH ₄ (1.2 g, 31.17 mmol) in THF (90 ml) was added dropwise a solution of tert-butyl 3-((1-ethoxy-2-methyl-1-oxopropan-2-yl )oxy)-1H-pyrazole-1-carboxylate (3.1 g, 10.39 mmol) in THF (20 ml) at 0°C under nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature and stirred for an additional 30 minutes. The reaction mixture was quenched by adding a saturated aqueous solution of Na ₂ SO ₄ . The resulting mixture was dried over Na ₂ SO ₄ . Solids were removed by filtration and the filtrate was concentrated to give 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol (1.5 g, yield: 92%), which was used in the next step without additional cleaning. ^1H NMR (400 MHz, CDCl ₃ ): δ=9.45 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 5.80 (d, J=2.4 Hz , 1H), 4.85 (s, 1H), 3.63 (s, 2H), 1.37 (s, 6H).

Step 4 - Synthesis of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate:

[750] Into a stirred solution of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol (1.1 g, 7.04 mmol) and triethylamine (2.93 mL, 21.13 mmol) in DCM (33 ml) was added MsCl (0.5 ml, 7.04 mmol) at 0°C under nitrogen atmosphere. After 1 hour, water (10 ml) was added. The aqueous layer was extracted with DCM (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (0 5% MeOH in DCM) to give 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate (600 mg, yield: 14%) as a yellow oil . MS: m/z 234.9 (M+H ⁺ ).

Step 5 - Synthesis of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole:

[751] To a solution of 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate (500 mg, 0.79 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 38 mg , 0.95 mmol) at 0°C in a nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature and stirred for an additional 12 hours. The reaction mixture was cooled to 0°C and a saturated aqueous solution of NH ₄ Cl (3 ml) was added. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (180 mg, yield: 50%) in the form of a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ): δ=7.36 (d, J=2.0 Hz, 1H), 5.30 (d, J=1.6 Hz, 1H), 4.03 (s , 2H), 1.63 (s, 6H).

Step 6 - Synthesis of 7-bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole:

[752] To a solution of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (150 mg, 1.09 mmol) in MeCN (5 ml) was added NBS (193 mg, 1.09 mmol) at 0°C. After addition, the reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to give 7-bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b] oxazole (120 mg, yield: 51%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.32 (s, 1H), 4.07 (s, 2H), 1.67 (s, 6H).

Step 7 - Synthesis of 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide:

[753] n-BuLi ( 2.5 M in hexane, 0.3 ml, 0.61 mmol) at -78°C under nitrogen. After 30 minutes, a solution of TrtNSO (186 mg, 0.61 mmol) in THF (1 ml) was added dropwise. The reaction mixture was left stirring at -78°C for 30 minutes, after which it was placed in an ice bath at 0°C, where it was stirred for an additional 10 minutes, tert-butyl hypochlorite (0.1 ml, 0.6 mmol) was added at 0°C. After 30 minutes, NH ₃ gas was bubbled through the mixture for 10 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-80% EtOAc in petroleum ether) to give 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7 -sulfonidamide (120 mg, yield: 50%) as a white solid. MS: m/z 481.1 (M+Na ⁺ ).

Step 8~9 - Synthesis of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5, 1-b]oxazole-7-sulfonimidamide:

[754] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b ]oxazole-7-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide (Example 100 and Example 101), replacing N'-trityl- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide on 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b] Oxazole-7-sulfonimidamide in step 3.

Step 10 - Synthesis of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[ 5,1-b]oxazol-7-sulfonidamide and (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2- dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (Example 139 and Example 140):

[755] N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b ]oxazole-7-sulfonidamide (60 mg, 0.14 mmol) was separated using chiral SLC (Phenomenex Cellulose 2 (250 mm * 30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 60 /40; 70 ml/min) to obtain (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl- 2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (method P, 4.31 min, peak 1, 21.5 mg, yield: 36%) and (R)-N'-((1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (method P , 4.91 min, peak 2, 17.5 mg, yield: 29%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[756] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.17 (s, 1H), 7.54 (s, 1H), 7.31 (s, 2H), 6, 85 (s, 1H), 4.15 (s, 2H), 2.77 (t, J=6.8 Hz, 4H), 2.68 (t, J=6.8 Hz, 4H), 1, 96-1.86 (m, 4H), 1.60 (d, J=5.6 Hz, 6H). MS: m/z 416.1 (M+H ⁺ ).

[757] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.17 (s, 1H), 7.54 (s, 1H), 7.29 (s, 2H), 6, 85 (s, 1H), 4.15 (s, 2H), 2.77 (t, J=7.2 Hz, 4H), 2.68 (t, J=6.8 Hz, 4H), 1, 96-1.88 (m, 4H), 1.60 (d, J=5.6 Hz, 6H). MS: m/z 416.1 (M+H ⁺ ).

Example 141 and Example 142

(R)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonidamide and (S)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide:

Step 1 - Synthesis of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene:

[758] Into a solution of 2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-amine (synthesis described in WO 2019023147, 20 mg, 0.13 mmol) and triethylamine (0.03 ml, 0 .19 mmol) in THF (0.5 ml) was added triphosgene (19 mg, 0.06 mmol) at room temperature. After 1 hour, the reaction mixture was filtered through a small pad of celite. The celite layer was washed with THF (2 ml). The filtrate was concentrated to give 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (20 mg, yield: 86%) as a light yellow oil.

Stage 2~3 Synthesis of N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonidamide:

[759] N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 102 and Example 103), replacing 3-isocyanato-2,4-diisopropyl-6-methoxypyridine with 3-isocyanato- 2,4,5,6-tetrahydro-1H-cyclobuta[f]indene in step 1. MS: m/z 388.0 (M+H ⁺ ).

Step 4 - Synthesis of (R)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazin-3-sulfonidamide and (S)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 141 and Example 142):

[760] N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonimidamide was purified using chiral SLC (Chiralpak AS (250 mm * 30 mm, 10 μm); supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 65/35; 70 ml/min) to give (R)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide (method C, 3.65 min, peak 1, 1 mg, yield: 9%) and (S)-N'-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamidium (method C, 3.87 min, peak 2, 1.1 mg, yield: 10%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[761] Peak 1: ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.68 (s, 1H), 6.72 (s, 2H), 4.48-4.44 (m, 2H), 4.18-4.14 (m, 2H), 3.25-3.20 (m, 2H), 2.98-2.95 (m, 2H), 2.91-2.87 (m, 2H ), 2.75-2.70 (m, 2H), 2.33-2.28 (m, 2H), 2.06-2.00 (m, 2H). MS: m/z 388.0 (M+H ⁺ ).

[762] Peak 2: ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.68 (s, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 4.48- 4.44 (m, 2H), 4.20-4.15 (m, 2H), 3.25-3.20 (m, 2H), 3.00-2.95 (m, 2H), 2, 90 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.08-2.02 (m, 2H). MS: m/z 388.0 (M+H ⁺ ).

Example 143, Example 144, Example 145 and Example 146

(S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5, 1-b]oxazole-7-sulfonidamide, (S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide, (R)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazol-7-sulfonidamide and (R)-N'-(((S)-3-methyl-1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide:

Step 1-2 - Synthesis of N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-
yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide:

[763] N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole -7-sulfonimidamide was prepared using the general procedure described for the preparation of (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3 -dihydropyrazolo[5,1-b]oxazol-7-sulfonidamide and (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2 ,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (Example 124 and Example 125), replacing 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene with 8-isocyanato -1-methyl-1,2,3,5,6,7-hexahydro-s-indacene in step 2.

Step 3 - Synthesis of (S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3- dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide, (S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide, (R)-N'-(((R)-3-methyl-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide and (R)-N'-(((S)-3-methyl -1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (Example 143, Example 144, example 145 and example 146):

[764] N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole -7-sulfonimidamide (200 mg, 0.50 mmol) was separated using chiral SLC (Chiralcel AD (250 mm * 30 mm, 5 μm), supercritical CO ₂ /MeOH + 0.1% NH ₄ OH = 65/35; 50 ml/min) to obtain (S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2 ,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide (method Q, 5.25 min, peak 1.4 mg, yield: 2%), (S)-N'-(((S)- 3-Methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (Method Q, 5.38 min, peak 2.5 mg, yield: 2.5%), ((R)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonidamide (method Q, 5.53 min, peak 3, 3 mg, yield: 1.5% ), (R)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydropyrazolo[ 5,1-b]oxazole-7-sulfonidamide (Method Q, 5.67 min, peak 4.5 mg, yield: 2.5%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[765] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.12 (s, 1H), 7.52 (s, 1H), 7.32 (s, 2H), 6, 84 (s, 1H), 5.22-5.12 (m, 2H), 4.33 (t, J=8.0 Hz, 2H), 2.89-2.72 (m, 5H), 2 .70-2.55 (m, 2H), 2.16-2.06 (m, 1H), 1.98-1.88 (m, 2H), 1.62-1.54 (m, 1H) , 1.04 (d, J=6.8 Hz, 3H). MS: m/z 402.2 (M+H ⁺ ).

[766] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.10 (s, 1H), 7.52 (s, 1H), 7.32 (s, 2H), 6, 84 (s, 1H), 5.21-5.15 (m, 2H), 4.32 (t, J=8.0 Hz, 2H), 2.86-2.72 (m, 5H), 2 .70-2.55 (m, 2H), 2.14-2.05 (m, 1H), 1.98-1.89 (m, 2H), 1.62-1.55 (m, 1H) , 1.03 (d, J=6.8 Hz, 3H) MS: m/z 402.2 (M+H ⁺ ).

[767] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.11 (s, 1H), 7.52 (s, 1H), 7.32 (s, 2H), 6, 84 (s, 1H), 5.21-5.15 (m, 2H), 4.32 (t, J=8.4 Hz, 2H), 2.87-2.74 (m, 5H), 2 .70-2.60 (m, 2H), 2.14-2.05 (m, 1H), 1.98-1.86 (m, 2H), 1.62-1.53 (m, 1H) , 1.03 (d, J=6.4 Hz, 3H). MS: m/z 402.1 (M+H ⁺ ).

[768] Peak 4: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.12 (s, 1H), 7.52 (s, 1H), 7.32 (s, 2H), 6, 84 (s, 1H), 5.23-5.16 (m, 2H), 4.33 (t, J=8.4 Hz, 2H), 2.89-2.73 (m, 5H), 2 .70-2.55 (m, 2H), 2.14-2.06 (m, 1H), 1.98-1.88 (m, 2H), 1.62-1.54 (m, 1H) , 1.04 (d, J=6.8 Hz, 3H). MS: m/z 402.2 (M+H ⁺ ).

Example 147, Example 148, Example 149 and Example 150

(S,6S)-6-methoxy-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S,6S)-6-methoxy-N'-(((S)-3-methyl-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide, (R,6S)-6-methoxy-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-6-methoxy-N'-(((S)-3-methyl-1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide

Step 1~2 - Synthesis of (6S)-6-methoxy-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[769] (6S)-6-methoxy-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide was prepared using the general procedure described for the preparation of (S)-N'-(((R)-3-methyl-1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimide amide, (S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide, (R)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro- 8-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-(((S) -3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonidamide (Example 126, Example 127, Example 128 and Example 129), replacing N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonidamide to (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide in step 4.

Step 3 - Synthesis of (S,6S)-6-methoxy-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (S,6S)-6-methoxy-N'-(((S)-3- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide, (R,6S)-6-methoxy-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R,6S)-6-methoxy-N'-(((S)-3- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide (Example 147, Example 148, Example 149 and Example 150):

[770] (6S)-6-methoxy-N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (80 mg, 0.18 mmol) was separated using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm), supercritical CO ₂ /EtOH + 0.1% NH ₄ OH = 55/45; 70 ml/min) to obtain (S,6S)-6-methoxy-N'-(((R)-3-methyl-1,2 ,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method I, 3.06 min, peak 1, 13.7 mg, yield: 17%), (S,6S)-6-methoxy-N'-(((S)-3-methyl-1,2,3, 5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (method I, 4 , 19 min, peak 2, 6.5 mg, yield: 8%), (R,6S)-6-methoxy-N'-(((R)-3-methyl-1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method I, 4.90 min , peak 3, 5.5 mg, yield: 7%) and (R,6S)-6-methoxy-N'-(((S)-3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method I, 6.08 min, peak 4 , 14 mg, yield: 18%), all as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[771] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.11 (s, 1H), 7.52 (s, 1H), 7.29 (s, 2H), 6, 84 (s, 1H), 4.60-4.56 (m, 1H), 4.30-4.15 (m, 3H), 4.04-4.01 (m, 1H), 3.28- 3.24 (s, 3H), 2.86-2.75 (m, 4H), 2.71-2.66 (m, 1H), 2.64-2.55 (m, 2H), 2. 18-2.06 (m, 1H), 1.96-1.87 (m, 2H), 1.59-1.54 (m, 1H), 1.03 (d, J=6.8 Hz, 3H). MS: m/z 446.1 (M+H ⁺ ).

[772] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.12 (s, 1H), 7.51 (s, 1H), 7.29 (s, 2H), 6. 84 (s, 1H), 4.60-4.56 (m, 1H), 4.31-4.16 (m, 3H), 4.04-4.01 (m, 1H), 3.28- 3.24 (m, 3H), 2.90-2.74 (m, 4H), 2.71-2.65 (m, 1H), 2.64-2.53 (m, 2H), 2. 15-2.06 (m, 1H), 1.99-1.85 (m, 2H), 1.59-1.54 (m, 1H), 1.04 (d, J=6.8 Hz, 3H). MS: m/z 446.2 (M+H ⁺ ).

[773] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.12 (s, 1H), 7.50 (s, 1H), 7.27 (s, 2H), 6, 84 (s, 1H), 4.60-4.56 (m, 1H), 4.31-4.15 (m, 3H), 4.04-4.01 (m, 1H), 3.28- 3.24 (m, 3H), 2.89-2.74 (m, 4H), 2.71-2.64 (m, 1H), 2.61-2.52 (m, 2H), 2. 16-2.07 (m, 1H), 2.00-1.84 (m, 2H), 1.61-1.53 (m, 1H), 1.05 (d, J=6.8 Hz, 3H). MS: m/z 446.2 (M+H ⁺ ).

[774] Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.11 (s, 1H), 7.50 (s, 1H), 7.24 (s, 2H), 6, 84 (s, 1H), 4.60-4.56 (m, 1H), 4.26-4.16 (m, 3H), 4.04-4.01 (m, 1H), 3.32- 3.31 (m, 3H), 2.86-2.75 (m, 4H), 2.73-2.67 (m, 1H), 2.63-2.55 (m, 2H), 2. 18-2.06 (m, 1H), 1.98-1.87 (m, 2H), 1.60-1.54 (m, 1H), 1.05 (d, J=6.8 Hz, 3H). MS: m/z 446.2 (M+H ⁺ ).

Example 151 and Example 152

(S,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2, 3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide

Step 1 - Synthesis of N-(2,3-dihydro-1H-inden-4-yl)pivalamide:

[775] Pivaloyl chloride (3 .1 ml, 24.8 mmol) at room temperature. After 1 hour, water (50 ml) was added. The aqueous layer was extracted with DCM (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2,3-dihydro-1H-inden-4-yl)pivalamide (4.8 g, yield: 98%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 2.96 (t, J=7.2 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H) , 2.26-2.05 (m, 2H), 1.33 (s, 9H). MS: m/z 218.2 (M+H ⁺ ).

Step 2 - Synthesis of N-(7-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide:

[776] To a solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (4.8 g, 22.1 mmol) in MeCN (40 ml) was added NBS (4.7 g, 26. 5 mmol) at room temperature. After 15 hours, the reaction mixture was concentrated under reduced pressure and the crude residue was dissolved in DCM (50 ml). The organic layer was washed with saturated aqueous Na ₂ CO ₃ (50 ml x 3), dried over Na ₂ SO ₄ , filtered and concentrated to give N-(7-bromo-2,3-dihydro-1H-inden-4-yl) pivalamide (6.5 g, yield: 99%) as a white solid, which was used in the next step without further purification. MS: m/z 296.1 (M+H ⁺ ).

Step 3 - Synthesis of 7-bromo-2,3-dihydro-1H-inden-4-amine:

[777] N-(7-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (6.5 g, 21.9 mmol) was dissolved in concentrated HCl (100 ml) and heated at 100°C in for 36 hours. After cooling to room temperature, water (50 ml) was added and the mixture was filtered. The solids were washed with EtOAc (20 ml x 3) to give 7-bromo-2,3-dihydro-1H-inden-4-amine (3). .44 g, yield: 74%) as a brown solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.41 (d, J=8.4 Hz). , 1H) 7.11 (d, J=8.0 Hz, 1H), 3.06 (t, J=7.6 Hz, 2H), 2.90 (t, J=7.2 Hz, 2H) , 2.13-1.99 (m, 2H). MS: m/z 212.0 (M+H ⁺ ).

Step 4 - Synthesis of 7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine:

[778] In a solution of 7-bromo-2,3-dihydro-1H-inden-4-amine (2.7 g, 12.7 mmol) in H ₂ O (5 ml) and 1,4-dioxane (40 ml ) added (2-methoxypyridin-4-yl)boronic acid (2.3 g, 15.3 mmol), K ₂ CO ₃ (5.3 g, 38.2 mmol) and Pd(dppf)Cl ₂ (0. 9 g, 1.3 mmol) under nitrogen atmosphere. The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H ₂ O (50 ml). The aqueous layer was extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified using a silica gel column (0-30% EtOAc in petroleum ether) to give 7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15 (d, J=5.2 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.95 (d, J=2.0, 5.2 Hz, 1H), 6.78 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 3.97 (s, 3H), 3, 74 (s, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.17-2.04 (m, 2H ). MS: m/z 241.0 (M+H ⁺ ).

Step 5 Synthesis of 4-(7-isocyanato-2,3-dihydro-1H-inden-4-yl)-2-methoxypyridine:

[779] In a solution of 7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (150 mg, 0.6 mmol) and triethylamine (0.1 ml, 0.7 mmol) in THF (5 ml) was added triphosgene (67 mg, 0.2 mmol) at room temperature. After 1 hour, the mixture was filtered through a pad of silica gel to remove triethylamine hydrochloride. The filtrate was concentrated to give 4-(7-isocyanato-2,3-dihydro-1H-inden-4-yl)-2-methoxypyridine (135 mg, 81%) as a yellow solid, which was used in the next step without further purification .

Step 6~7 - Synthesis of (6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[780] (6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-sulfonidamide and (R)-N'-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3- sulfonidamide (Example 100 and Example 101), replacing N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-sulfonidamide and 4-isocyanato-1,2, 3,5,6,7-hexahydro-s-indacene on (6S)-6-methoxy-N'-trityl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonidamide and 4-(7-isocyanato-2,3-dihydro-1H-inden-4-yl)-2-methoxypyridine in step 3.

Step 8 - Synthesis of (S,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl )-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 151 and Example 152):

[781] (6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (60 mg, 0.12 mmol) was separated using chiral SLC (Chiralcel OJ (250 mm * 30 mm, 5 μm), supercritical CO ₂ /IPA + 0.1% NH ₄ OH = 60/40; 60 ml/min), obtaining (S,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl) )-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (method R, 1 ,84 min, peak 1.4 mg, yield: 5%) and (R,6S)-6-methoxy-N'-((7-(2-methoxypyridin-4-yl)-2,3-dihydro-1H -inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Method R, 2.25 min, peak 2.5 mg , yield: 5%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[782] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.24 (s, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.64- 7.60 (m, 2H), 7.36 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.81 (s, 1H), 4.62-4.58 (m, 1H), 4.32-4.18 (m, 3H), 4.05-4.01 (m, 1H), 3. 87 (s, 3H), 3.41-3.37 (m, 3H), 2.94 (t, J=7.6 Hz, 2H), 2.85-2.80 (m, 2H), 1 .99-1.91 (m, 2H). MS: m/z 499.1 (M+H ⁺ ).

[783] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.25 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.65- 7.60 (m, 2H), 7.40 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=5.6 Hz, 1H), 6.81 (s, 1H), 4.62-4.58 (m, 1H), 4.34-4.18 (m, 3H), 4.05-4.01 (m, 1H), 3. 87 (s, 3H), 3.37-3.36 (m, 3H), 2.94 (t, J=7.6 Hz, 2H), 2.85-2.80 (m, 2H), 1 .99-1.90 (m, 2H). MS: m/z 499.1 (M+H ⁺ ).

Example 153, Example 154, Example 155 and Example 156

(S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (R)-N'-(((S)-2-fluoro-1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide, (S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R)-N'-(((R)-2-fluoro-1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide

Step 1 Synthesis of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol:

[784] NaBH ₄ (6 .9 g, 181.84 mmol) at 0°C in a nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature. After 1 hour, the solvent was removed in vacuo and H ₂ O (10 ml) was added to the crude residue. The aqueous layer was extracted with EtOAc (20 ml x 2). The combined organic layers were washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (15% EtOAc in petroleum ether) to give 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (7.5 g, yield : 94%) as a light yellow oil.

Step 2 Synthesis of 8-nitro-1,2,3,5-tetrahydro-s-indacene:

[785] TsOH (3.3 g, 17 mmol) was added to a flask equipped with a Dean-Stark trap containing a solution of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (7.5 g, 34.21 mmol) in toluene (100 ml). The reaction mixture was stirred at 110°C for 2 hours. After cooling to room temperature, the mixture was diluted in EtOAc (50 ml). The organic layer was washed with saturated aqueous NaHCO ₃ (100 ml×2), brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was triturated with hexane to give 8-nitro-1,2,3,5-tetrahydro-s-indacene (5.9 g, yield: 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ=7.53 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 6.79-6.77 (m, 1H), 3 .45 (s, 2H), 3.35 (t, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.21-2.16 (m, 2H).

Step 3 - Synthesis of 2-nitro-1a,3,4,5,7,7a-hexahydro-s-indaceno[1,2-b]oxyrene:

[786] To a solution of 8-nitro-1,2,3,5-tetrahydro-s-indacene (5.9 g, 29.32 mmol) in DCM (80 ml) was added 85% t-CPBA (9.7 g , 38.12 mmol) at 0°C in a nitrogen atmosphere. After addition, the reaction mixture was allowed to warm to room temperature. After 12 hours, the reaction mixture was washed with saturated aqueous NaHCO ₃ solution (80 ml) and Na ₂ S ₂ O ₃ solution (80 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified using a silica gel column (10% EtOAc in petroleum ether) to give 2-nitro-1a,3,4,5,7,7a-hexahydro-s-indaceno[1,2-b]oxyrene (4,2 g, yield: 66%) as a white solid.

Step 4 - Synthesis of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-2-ol:

[787] A solution of 2-nitro-1a,3,4,5,7,7a-hexahydro-s-indaceno[1,2-b]oxyrene (4.0 g, 18.41 mmol) in EDC (60 ml ) Znl ₂ (8.8 g, 27.62 mmol) and NaBH ₃ CN (9.3 g, 147.32 mmol) were added at room temperature. The reaction mixture was heated to 80°C for 4 hours. After cooling to room temperature, the mixture was poured into 6 N aqueous HCl solution (10 ml). The aqueous layer was extracted with DCM (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by a silica gel column (20% EtOAc in petroleum ether) to give 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-2-ol (3.4 g, 84% yield ) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.43 (s, 1H), 4.94 (s, 1H), 4.51 (s, 1H), 3.29-3.25 (m , 1H), 3.18-3.05 (m, 4H), 2.89 (t, J=7.6 Hz, 2H), 2.83-2.75 (m, 1H), 2.10- 2.04 (m, 2H).

Step 5 - Synthesis of 2-fluoro-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene:

[788] To a solution of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-2-ol (800 mg, 3.65 mmol) in DCM (20 ml) add DAST ( 1.50 ml, 10.95 mmol) at 0°C in a nitrogen atmosphere. After 1 hour, saturated aqueous Na ₂ CO ₃ solution (5 ml) was carefully added. The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by a silica gel column (15% EtOAc in petroleum ether) to give 2-fluoro-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene (370 mg, yield: 46%) in the form of a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ=7.39 (s, 1H), 5.63-5.45 (m, 1H), 3.70-3.63 (m, 2H), 3.58 -3.25 (m, 4H), 3.21-2.98 (m, 2H), 2.18-2.13 (m, 2H).

Step 6 Synthesis of 2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine:

[789] Mixture of 2-fluoro-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene (370 mg, 1.67 mmol) and 10% Pd on carbon (178 mg, 1.67 mmol) 67 mmol) in EtOH (8 ml) was stirred at room temperature under a hydrogen atmosphere (15 psi). After 2 hours, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give 2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (350 mg, crude) as a yellow oil, which was used in the next step without further cleaning.

¹ H NMR (400 MHz, CDCl ₃ ) δ=6.65 (s, 1H), 5.60-5.44 (m, 1H), 3.52 (s, 2H), 3.23-3.13 (m, 2H), 3.07-2.95 (m, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H) , 2.15-2.05 (m, 2H). MS: m/z 192.1 (M+H ⁺ ).

Step 7 Synthesis of 2-fluoro-4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene:

[790] In a solution of 2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (150 mg, 0.78 mmol) and triethylamine (0.11 ml, 0.78 mmol) in anhydrous THF (9 ml) was added triphosgene (93 mg, 0.31 mmol) at room temperature. The reaction mixture was stirred at 70°C for 2 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel to remove triethylamine hydrochloride. The filtrate was used directly in the next step.

Step 8~9 - Synthesis of N'-((2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7- Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide:

[791] N'-((2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl )carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (S)-N'-((2,4- diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide (Example 76 and Example 77), replacing 3-isocyanato-2,4-diisopropyl-6-methoxy-pyridine with 2-fluoro-4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene in step 3.

Step 10 - Synthesis of (S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6- dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide, (R)-N'-(((8)-2-fluoro-1,2, 3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonidamide, (S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6- dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide and (R)-N'-(((R)-2-fluoro-1,2, 3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-sulfonimidamide (Example 153, Example 154, Example 155, and Example 156):

[792] N'-((2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (180 mg, 0.40 mmol) was purified using chiral SLC (Chiralpak AD (250 mm * 30 mm, 10 μm); supercritical CO ₂ /EtOH + 0.1% NH ₄ OH=55/45; 60 ml/min) to obtain (S)-N'-(((S)-2-fluoro-1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (method G, 4.97 min, peak 3, peak 3, 21.3 mg, yield: 12%), (R)-N'-(((S)-2-fluoro-1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (method G, 5.27 min, peak 4, 10.8 mg, yield: 6%) and N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene- 4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (mixture of peak 1 and peak 2, 44 mg, yield: 24%), all as white solids. N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (mixture of peak 1 and peak 2, 44 mg) was purified using chiral SLC (Chiralcel OJ (250 mm * 30 mm, 5 μm); supercritical CO ₂ /IPA + 0.1% NH ₄ OH=75/25, 60 ml/min) to obtain (S)-N'-(((R)-2-fluoro-1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide ( method G, 4.14 min, peak 1, 11.2 mg, yield: 25%) and (R)-N'-(((R)-2-fluoro-1,2,3,5,6,7 -hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonimidamide (method G, 4.73 min, peak 2, 14 mg, 32% yield, both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[793] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.30 (s, 1H), 7.55 (s, 1H), 7.26 (s, 2H), 6.91 ( s, 1H), 5.53-5.33 (m, 1H), 4.07 (s, 2H), 3.87 (s, 2H), 3.23-2.84 (m, 4H), 2 .84-2.63 (m, 4H), 1.99-1.88 (m, 2H), 1.04 (s, 6H). MS: m/z 448.1 (M+H ⁺ ). Connection 155

[794] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.28 (s, 1H), 7.55 (s, 1H), 7.27 (s, 2H), 6.91 ( s, 1H), 5.55-5.33 (m, 1H), 4.07 (s, 2H), 3.86 (s, 2H), 3.25-2.85 (m, 4H), 2 .84-2.60 (m, 4H), 2.01-1.87 (m, 2H), 1.03 (d, J=6.8 Hz, 6H). MS: m/z 448.1 (M+H ⁺ ). Connection 156

[795] Peak 3: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.27 (s, 1H), 7.55 (s, 1H), 7.27 (s, 2H), 6. 91 (s, 1H), 5.55-5.30 (m, 1H), 4.10 (s, 2H), 3.86 (s, 2H), 3.24-2.83 (m, 4H) , 2.81-2.65 (m, 4H), 2.00-1.87 (m, 2H), 1.03 (d, J=6.8 Hz, 6H). MS: m/z 448.1 (M+H ⁺ ). Connection 153

Peak 4: ^1H NMR (400 MHz, DMSO- _d6 ): δ=8.29 (s, 1H), 7.55 (s, 1H), 7.26 (s, 2H), 6.91 (s , 1H), 5.55-5.30 (m, 1H), 4.07 (s, 2H), 3.87 (s, 2H), 3.23-2.85 (m, 4H), 2, 84-2.60 (m, 4H), 1.99-1.90 (m, 2H), 1.04 (s, 6H). MS: m/z 448.1 (M+H ⁺ ). Connection 154

Example 157 and Example 158

(S)-N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-3-sulfonidamide and (R)-N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

Step 1 Synthesis of N-(2,3-dihydrobenzofuran-4-yl)acetamide:

[796] A mixture of 2,3-dihydrobenzofuran-4-amine (4.0 g, 29.6 mmol) in acetic anhydride (40 ml, 59.2 mmol) was stirred at room temperature. After 16 hours, the reaction mixture was concentrated to give N-(2,3-dihydrobenzofuran-4-yl)acetamide (3.4 g, yield: 65%) as a white solid, which was used in the next step without further purification. MS: m/z 178.0 (M+H ⁺ ).

Step 2 - Synthesis of N-(5-bromo-2,3-dihydrobenzofuran-4-yl)acetamide:

[797] To a solution of N-(2,3-dihydrobenzofuran-4-yl)acetamide (3.4 g, 19.2 mmol) in DCM (70 ml) NBS (3.76 g, 21.1 mmol) was added portionwise. at 0°C in a nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was concentrated and the crude residue was purified using a silica gel column (1% MeOH in DCM) to give N-(5-bromo-2,3-dihydrobenzofuran-4-yl)acetamide (3.3 g, yield: 67%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 6.58 (d, J=8.4 Hz, 1H ), 4.61 (t, J=8.8 Hz, 2H), 3.22 (t, J=8.8 Hz, 2H), 2.23 (s, 3H).

Step 3 Synthesis of 5-bromo-2,3-dihydrobenzofuran-4-amine:

[798] A mixture of N-(5-bromo-2,3-dihydrobenzofuran-4-yl)acetamide (3.3 g, 12.9 mmol) and NaOH (5.15 g, 128.9 mmol) in water (500 ml) and EtOH (100 ml) was heated at 90°C under nitrogen atmosphere. After 80 hours, the reaction mixture was concentrated to remove EtOH. The residue was filtered and the white solid was dissolved in ethyl acetate (60 ml) and water (10 ml). The pH was adjusted to 2.0 by adding concentrated HCl. The resulting solid was filtered to obtain 5-bromo-2,3-dihydrobenzofuran-4-amine (1.7 g, yield: 62%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.06 (d, J=8.4 Hz, 1 H), 6.00 (d, J=8.4 Hz, 1 H), 4.50 (t, J=8.8 Hz, 2 N), 3.01 (t, J=8.8 Hz, 2 N).

Step 4 - Synthesis of 5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine:

[799] To a solution of 5-bromo-2,3-dihydrobenzofuran-4-amine (1.7 g, 7.94 mmol) in 1,4-dioxane (95 ml) and water (15 ml) was added 2-methoxypyridine- 4-boronic acid (1.46 g, 9.53 mmol), Pd(dppf)Cl ₂ (581 mg, 0.79 mmol) and Na ₂ CO ₃ (2.52 g, 23.8 mmol) under nitrogen atmosphere . The resulting mixture was heated at 80°C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The crude residue was purified using a silica gel column (10-20% EtOAc in petroleum ether) to give 5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine (1.8 g, yield: 94% ) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J=5.2 Hz, 1H), 7.00-6.98 (m, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.77 (s, 1H), 6.13 (d, J=8.0 Hz, 1H), 4.92 (s, 2H), 4.53 (t, J= 8.8 Hz, 2H), 3.86 (s, 3H), 3.00 (t, J=8.8 Hz, 2H).

Step 5 Synthesis of 4-(4-isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine:

[800] In a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine (150 mg, 0.62 mmol) and triethylamine (0.26 ml, 1.86 mmol) in THF (30 ml) triphosgene (74 mg, 0.25 mmol) was added in one part at 0°C under a nitrogen atmosphere. After 1 hour, the reaction mixture was filtered through a pad of silica gel to remove triethylamine hydrochloride. The filtrate containing 4-(4-isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine was used directly in the next step.

Step 6-7 - Synthesis of N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonidamide:

[801] N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonimidamide was prepared using the general procedure described for the preparation of (S)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((2,4-diisopropyl-6-methoxypyridin-3-yl)carbamoyl)-6,7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 102 and Example 103), replacing 3-isocyanato-2,4-diisopropyl-6-methoxypyridine with 4-(4 -isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine in step 1. MS: m/z 471.2 (M+H ⁺ ).

Step 8 - Synthesis of (S)-N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazin-3-sulfonidamide and (R)-N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (Example 157 and Example 158):

[802] N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonidamide (95 mg, 0.20 mmol) was separated using chiral SLC (Phenomenex Cellulose-2 (250 mm * 30 mm, 10 μm); supercritical CO ₂ /MeOH + 0.1% NH ₄ OH=45/55; 70 ml/min) to obtain (S)-N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonidamide (method G, 8.12 min, peak 1, 25.4 mg, yield: 26%) and (R) -N'-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonidamide (Method G, 10.22 min, peak 2, 30.8 mg, yield: 31%), both as white solids. Stereochemistry was randomly assigned to each stereoisomer.

[803] Peak 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.19 (s, 1H), 8.09 (d, J=5.2 Hz, 1H), 7.41 (s , 1H), 7.23 (s, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.92 (d, J=5.2 Hz, 1H), 6.74 (s , 1H), 6.70 (d, J=8.0 Hz, 1H), 4.56 (t, J=8.8 Hz, 2H), 4.37 (t, J=4.8 Hz, 2H ), 4.11 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.11-3.06 (m, 2H), 2.22-2.13 (m, 2H). MS: m/z 471.1 (M+H ⁺ ).

[804] Peak 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.18 (s, 1H), 8.09 (d, J=5.2 Hz, 1H), 7.41 (s , 1H), 7.22 (s, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.92 (d, J=5.2 Hz, 1H), 6.74 (s , 1H), 6.70 (d, J=8.0 Hz, 1H), 4.56 (t, J=8.8 Hz, 2H), 4.37 (t, J=4.4 Hz, 2H ), 4.11 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.11-3.06 (m, 2H), 2.24-2.11 (m, 2H). MS: m/z 471.1 (M+H ⁺ ).

Biological research methods

Abbreviations

PBMC: peripheral blood mononuclear cells

KC: Kupffer cells

FBS: fetal bovine serum

L PS: lipopolysaccharides

NLRP3 Activation and Inhibition Assays

[805] Some of the following assays were used to determine the inhibitory activity of the compounds on the NLRP3 inflammasome using a common inflammasome activation stimulus, nigericin.

Example B1: Cell culture

[806] Human peripheral blood mononuclear cells (PBMCs), consisting of lymphocytes (T, B and NK cells), monocytes and dendritic cells, were freshly isolated from human peripheral blood from healthy donors. Cells were obtained through an IRB-approved donor program from iXCells Biotechnologies, in which all donors were tested for bacterial and viral infections. Cells were purified from peripheral blood using Ficoll gradient centrifugation.

[807] Human Kupffer cells (KCs), specialized hepatic macrophages residing in the space of Disse, were obtained by gradient isolation from liver samples collected postmortem by Samsara Sciences. Cells were obtained through an IRB-approved donor program from Samsara Sciences in which all donors tested negative for bacterial and viral infections.

Biological Example B2: NLRP3 Inflammasome Activation Assays

[808] Fresh or cryopreserved PBMCs were seeded into a 96-well V-bottom plate at 0.5-1×10 ⁵ cells per well and incubated overnight at 37°C with 5% CO ₂ in RPMI 1640 supplemented GlutaMAX, 4.5 g/L D-glucose, 10% fetal bovine serum (FBS), 100 mM sodium pyruvate, 1% penicillin/streptomycin, 10 mM GEPES and 0.05 mM β-mercaptoethanol. Fresh or cryopreserved CK cells were seeded into 96-well flat-bottom plates at 0.6-1.5 x 10 ⁵ cells/well and incubated overnight at 37°C, 5% CO ₂ in RPMI 1640 medium supplemented with GlutaMAX, PBS, 1% penicillin/streptomycin and 10 mM GEPES. The next day, the cells were primed with 100 ng/ml lipopolysaccharides (LPS; Sigma Aldrich) in PBS-free RPMI 1640 for 3 hours. After the priming step, the medium was removed, and PBMCs were preincubated with serial concentrations of the test compounds (0.00017 10 μM) or carrier (DMSO) for 30 min in a PBS-free medium before adding the NLRP3 activator. Cells were then stimulated with 10 μM nigericin (Sigma Aldrich; InvivoGen) for 1.5 h. The plates were centrifuged at 1500 rpm for 3 min to pellet the cells, and the supernatant was transferred to new plates for subsequent experiments.

Cytokine measurement/NLRP3 inflammasome activity assessment

[809] For ELISA analysis, cells were seeded in 96-well plates. After the assay, supernatants were discarded, and the levels of mature IL-1β, IL18, and TNFα (Quantikine ELISA, R&D systems) in conditioned cell media were measured by ELISA according to the manufacturer's instructions.

Example B3: CTG Analysis (CellTitre-Glo)

[810] The viability of compound-treated cells was measured using the CellTiter-Glo® assay (Promega, Madison, WI), which measures the ATP content of cells, which is proportional to the number of living cells in the well. This is a counter-study to determine that the reduction in IL-1β levels in LPS-nigericin-stimulated and compound-treated cells is not due to cytotoxicity, but rather to inhibition of the inflammasome pathway. Compounds that inhibit NRLP3 inflammasome activation ultimately increase the viability of LPS- and nigericin-stimulated cells by blocking NRLP3-mediated pyroptosis, which would otherwise lead to cell lysis.

Example B4: TNF-α

[811] TNFα levels in LPS- and nigericin-stimulated cells were measured using the HTRF assay (Cisbio, Bedford, MA). Inflammasome pathway-selective compounds do not inhibit TNFα production, which is solely dependent on LPS stimulation and occurs through the TLR4/NFkB pathway. Measuring TNF-alpha production also serves as a technical counter-test to eliminate compounds that interact with HTRF reagents. Thus, compounds that inhibit both IL-1β and TNFα levels are categorized as being nonselective for the inflammasome and confounding HTRF results.

Analytical results

[812] The results of certain compounds are shown below. In the table below A: <100 nM; B: 100 nM - 1 µM; C: 1-10 µM; D: >10 µM.

Example B5: HTRF assay for IL-1β PBMCs

Cell culture and NLRP3 inflammasome activation assay: [813] Human frozen PBMCs were purchased from StemCells Technologies. Cells were quickly thawed in a water bath at 37°C and resuspended in fresh assay medium consisting of RPMI 1640 medium containing 1% sodium pyruvate, 10 mM HEPES, 2.5 g/L glucose, and 55 μM 2-mercaptoethanol. The cell density was adjusted to 8.1 × ¹⁰⁵ cells/ml. Cells were primed by adding lipopolysaccharide (Invivogen, ultrapure lipopolysaccharide from E. coli, tlrl-3pelps) at a final concentration of 100 ng/ml in the cell suspension. 37 μl of cell suspension with LPS was seeded into the wells of a 384-well plate and incubated for 3 hours at 37°C and 5% CO ₂ . After priming, PBMCs were preincubated with serially diluted test compounds at an initial concentration of 40 μM, followed by a 2-fold dilution for a 20-point curve or with vehicle (DMSO) for 30 min in analytical medium at 37°C and 5% CO ₂ . Cells were stimulated with 10 μM nigericin (Invivogen, tlrl-nig-5) for 90 min at 37°C and 5% CO ₂ to activate the NLRP3-3aBHCHMoro inflammasome pathway and release IL-1β into the cell culture supernatant. Cells were centrifuged at 1200 rpm for 1 min and 40 μl of supernatant was transferred to fresh plates and stored at -80°C until IL-1β analysis.

HTRF analysis of IL-1β

[814] 16 μL of supernatant was added to white 384-well HTRF plates, followed by the addition of 4 μL of HTRF cocktail to each well. The plates were quickly centrifuged, sealed, and incubated overnight at room temperature. The next day, the HTRF signal was read on Pherastar and the 665/620 ratio was calculated based on the manufacturer's protocol to obtain the concentration of IL-1β in the cell culture supernatant.

Example P36: THP-1 ASC-GFP speck Cell culture:

[815] The THP-1 ASC-GFP cell line was purchased from Invivogen, San Diego, for the inflammasome activation assay. THP-1 ASC-GFP cells stably express a 37.6 kDa ASC::GFP fusion protein, which makes it possible to monitor spec formation by microscopy following activation of the NLRP3-dependent inflammasome pathway. Cells were maintained at a density of 600,000 cells/ml in growth medium consisting of RPMI 1640, 2 mM L-glutamine, 25 mM GEPES and 10% heat-inactivated fetal bovine serum at 37°C and 5% CO ₂ . Cells were passaged every 3-4 days and used for analysis for up to 20 passages.

NLRP3 inflammasome activation assay:

[816] THP-1 ASC-GFP cells were harvested by centrifuging the cells at 800 rpm for 5 minutes. The cell culture supernatant was removed and the cells were resuspended in fresh medium at a density of 1×10 ⁶ cells/ml in an assay medium consisting of RPMI 1640, 2 mM L-glutamine, 25 mM GEPES and 10% heat-inactivated fetal bovine serum. Phorbol 12-myristate 13-acetate (PMA) (Invivogen, tlrl-pma) was added to the cell suspension at a final concentration of 500 ng/ml and mixed thoroughly. 40,000 cells per well of a 384-well plate were added and differentiated into macrophages overnight at 37°C and 5% CO ₂ . Cells were primed with 1 μg/ml lipopolysaccharide (Invivogen, ultrapure lipopolysaccharide from E. coli, tlrl-3pelps) in assay medium for 3 hours at 37°C and 5% CO ₂ . After priming, the medium was removed, and THP-1 ASC-GFP cells were preincubated with serially diluted test compounds at an initial concentration of 40 μM, followed by a 2-fold dilution for a 20-point curve or with vehicle (DMSO) for 30 min in assay medium at 37°C and 5% CO ₂ . Cells were then stimulated with 10 μM nigericin (Invivogen, tlrl-nig-5) for 90 min at 37°C and 5% CO ₂ to activate the NLRP3-dependent inflammasome pathway and spec formation. After stimulation, cells were fixed with 4.8% paraformaldehyde (Electron Microscopy Sciences, #15710-S) and incubated at room temperature for 15 min. Cells were then washed 3 times with 100 μl of phosphate-buffered saline and permeabilized in the presence of permeabilization/blocking buffer for 20 min at room temperature. Cells were washed 3 times with 100 μl of phosphate-buffered saline and incubated for 1 h at room temperature in the presence of Hoechst dye. After staining with Hoechst dye, cells were washed 3 times with 100 μl of phosphate-buffered saline and visualized for the formation of ASC spec.

Visualization of ASC-GFP speck:

[817] THP-1 ASC-GFP cells were imaged on 488 and Hoechst channels. The Hoechst channel was used to count cells, and channel 488 was used to determine the number of GFP ASC speck in the imaged fields. The percentage of cells with spec was calculated by dividing the number of GFP-positive spots by the total number of cells.

[818] Additional analytical results are shown in Table B1-a, Table B1-b and Table B1-c.

Equivalents

[819] Although the present invention has been described in connection with the specific embodiments set forth herein, many alternatives will be apparent to those skilled in the art.

options and their other variations. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (83)

1. A compound having the structure of formula (I-5) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰⁰ is selected from the group consisting of H, -CN, -C(O)R ^3b and C ₁ -C ₆ alkyl; R ^l is selected from the group consisting of R ^1z represents H; R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are each independently selected from the group consisting of H, -OR ^11a , -NR ^11a R ^12a , C ₁ -C ₆ alkyl or a 4-membered heterocyclyl with one ring heteroatom selected from nitrogen, wherein said 4-membered heterocyclyl is unsubstituted or is substituted with one or more substituents selected from -OR ^11a ; R ² is selected from the group consisting of a 5-membered heteroaryl with two ring heteroatoms selected from nitrogen, wherein said 5-membered heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and -(CH ₂ ) _1-4 C ₃ -C ₁₀ cycloalkyl; R ^2a is H, halogen or -C(O)OR ^15a ; each of R ^2b , R ^2c , R ^2d , R ^2e and R ^2f independently represents H, halogen, -OR ^17a , -C(O)R ^17b , C ₁ -C ₆ alkyl or 5-6 membered heteroaryl with one a ring heteroatom selected from nitrogen, wherein the C ₁ -C ₆ alkyl and said 5-6 membered heteroaryl are unsubstituted or are substituted with one or more substituents selected from the group consisting of -OR ^17a and -NR ^17a R ^18a ; or two adjacent R ^2b , R ^2c , R ^2e and R ^2f together with the atoms to which they are attached can form a C ₃ -C ₁₀ cycloalkyl or 3-7-membered heterocyclyl with one ring heteroatom selected from oxygen, where C ₃ - The C ₁₀ cycloalkyl and said 3-7 membered heterocyclyl are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ alkyl; R ^11a , R ^12a , R ^15a , R ^17a and R ^18a are each independently H or C ₁ -C ₈ alkyl, wherein the C ₁ -C ₈ alkyl is unsubstituted or is substituted with one or more substituents selected from the group consisting of from halogen, -OC ₁ -C ₆ alkyl and -NH(C ₁ -C ₆ alkyl); And R ^3b and R ^17b are independently in each case -OH or C ₁ -C ₈ alkyl. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ² represents 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein X ² is CR ^2a and R ^2a is H, halogen or -C(O)OR ^15a . 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ² represents 5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, where X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; X ⁵ represents CR ^2e ; And R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently selected from the group consisting of H, halogen, -OR ^17a , C ₁ -C ₆ alkyl and 5-6 membered heteroaryl with one ring heteroatom selected from nitrogen; wherein C ₁ -C ₆ alkyl and said 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of -OR ^17a and -NR ^17a R ^18a . 6. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, where X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; X ⁵ represents CR ^2e ; And R ^2b , R ^2c , R ^2d , R ^2e and R ^2f are each independently selected from the group consisting of H, halogen and C ₁ -C ₆ alkyl. 7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, where X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; X ⁵ represents CR ^2e ; R ^2b and R ^2c together with the atoms to which they are attached form a C ₃ -C ₁₀ cycloalkyl or 3-7 membered heterocyclyl with one ring heteroatom selected from oxygen, where C ₃ -C ₁₀ cycloalkyl or the specified 3-7- the heterocyclyl member is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ alkyl; And each R ^2d , R ^2e and R ^2f are independently selected from the group consisting of H, halogen, -OR ^17a , C ₁ -C ₆ alkyl and 5-6 membered heteroaryl with one ring heteroatom selected from nitrogen, where each C ₁ -C ₆ alkyl and said 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of -OR ^17a and -NR ^17a R ^18a . 8. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, where X ³ represents CR ^2c ; X ⁴ represents CR ^2d ; X ⁵ represents CR ^2e ; R ^2b and R ^2c together with the atoms to which they are attached form a C ₃ -C ₁₀ cycloalkyl, wherein the C ₃ -C ₁₀ cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ alkyl; R ^2e and R ^2f together with the atoms to which they are attached form a C ₃ -C ₁₀ cycloalkyl, wherein the C ₃ -C ₁₀ cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ alkyl; And R ^2d represents H, halogen or C ₁ -C ₆ alkyl. 9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of 10. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, where each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h , if present, is independently selected from the group consisting of H, -OR ^11a , -NR ^11a R ^12a , C ₁ -C ₆ alkyl or 4-membered heterocyclyl with one ring heteroatom selected from nitrogen. 11. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, where each of R ^la , R ^1b , R ^lc , R ^ld , R ^le , R ^lf , R ^1g and R ^1h , if present, is independently selected from the group consisting of H, -OR ^11a , -NR ^11a R ^12a , C ₁ -C ₆ alkyl and 4-membered heterocyclyl with one ring heteroatom selected from nitrogen, where said 4-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from -OR ^11a . 12. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, where R ¹ represents R ^1z represents H and R ¹⁰⁰ represents H. 13. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, where R ¹ represents R ^1z represents H and R ¹⁰⁰ represents H. 14. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, where R ¹ represents R ^1z represents H and R ¹⁰⁰ represents H. 15. Connection according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of and R ^1z represents H. 16. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 17. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 18. Connection according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt thereof, wherein said compound has the formula 19. Connection according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt thereof, wherein said compound has the formula 20. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 1, which is or or a pharmaceutically acceptable salt thereof. 23. The compound according to claim 1, which is 24. A pharmaceutical composition for inhibiting an inflammasome, such as the NLRP3 inflammasome, containing a compound according to any one of paragraphs. 1-23 or a pharmaceutically acceptable salt thereof in an effective amount and a pharmaceutically acceptable carrier.